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Yu L, Wu Q, Jiang S, Liu J, Liu J, Chen G. Controversial Roles of Regenerating Family Proteins in Tissue Repair and Tumor Development. Biomedicines 2024; 13:24. [PMID: 39857608 PMCID: PMC11762848 DOI: 10.3390/biomedicines13010024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
Background: Over the past 40 years since the discovery of regenerating family proteins (Reg proteins), numerous studies have highlighted their biological functions in promoting cell proliferation and resisting cell apoptosis, particularly in the regeneration and repair of pancreatic islets and exocrine glands. Successively, short peptides derived from Reg3δ and Reg3α have been employed in clinical trials, showing favorable therapeutic effects in patients with type I and type II diabetes. However, continued reports have been limited, presumably attributed to the potential side effects. Methods: This review summarizes extensive research on Reg proteins over the past decade, combined with our own related studies, proposing that Reg proteins exhibit dimorphic effects. Results: The activity of Reg proteins is not as simplistic as previously perceived but shows auto-immunogenicity depending on different pathophysiological microenvironments. The immunogenicity of Reg proteins could recruit immune cells leading to an anti-tumor effect. Such functional diversity is correlated with their structural characteristics: the N-terminal region contributes to autoantigenicity, while the C-type lectin fragment near the C-terminal determines the trophic action. It should be noted that B-cell masking antigens might also reside within the C-type lectin domain. Conclusions: Reg proteins have dual functional roles under various physiological and pathological conditions. These theoretical foundations facilitate the subsequent development of diagnostic reagents and therapeutic drugs targeting Reg proteins.
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Affiliation(s)
- Luting Yu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Qingyun Wu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Shenglong Jiang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Jia Liu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Junli Liu
- MeDiC Program, The Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
| | - Guoguang Chen
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
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Zhou YH, Yu LT, Wang XN, Li YJ, Xu KY, Li X, Pu CC, Xie FL, Xie BB, Gao Y, Luo C. Reg2 treatment is protective but the induced Reg2 autoantibody is destructive to the islets in NOD mice. Biochem Pharmacol 2024; 227:116444. [PMID: 39038551 DOI: 10.1016/j.bcp.2024.116444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 07/14/2024] [Accepted: 07/18/2024] [Indexed: 07/24/2024]
Abstract
Regenerating family protein 2 (Reg2) is a trophic factor which stimulates β-cell replication and resists islet destruction. However, Reg2 also serves as an islet autoantigen, which makes it complicated to judge the effectiveness in treating diabetes. How Reg2 treatment behaves in non-obese diabetic (NOD) mice is to be investigated. NOD mice were treated with recombinant Reg2 protein, Complete Freund's adjuvant (CFA) + PBS and CFA+Reg2 vaccinations, CFA+PBS- and CFA+Reg2-immunized antisera, and single chain variable fragment (scFv)-Reg2 and mIgG2a-Reg2 antibodies. Glycemic level, bodyweight, serum Reg2 antibody titer, glucose tolerance, and insulin secretion were determined. Islet morphological characteristics, insulitis, cell apoptosis, islet cell components, and T cell infiltration were analyzed by histological examinations. The autoantigenicity of constructed Reg2C and Reg2X fragments was determined in healthy BALB/c mice, and the bioactivity in stimulating cell proliferation and survival was assessed in insulinoma MIN6 cells. Reg2 administration alleviated diabetes in NOD mice with improved glucose tolerance and insulin secretion but elevated serum Reg2 autoantibodies. Histomorphometry showed reduced inflammatory area, TUNEL signal and CD8 + T cell infiltration, and increased β-cell proportion in support of the islet-protective effect of Reg2 treatment. CFA+PBS and CFA+Reg2 immunizations prevented diabetic onset and alleviated insulitis while injections of the antisera offered mild protections. Antibody treatments accelerated diabetic onset without increasing the overall incidence. Reg2C fragment depletes antigenicity, but reserves protective activity in streptozotocin (STZ)-treated MIN6 cells. In conclusion, Reg2 treatment alleviates type 1 diabetes (T1D) by preserving islet β-cells, but induces Reg2 autoantibody production which poses a potential risk of accelerating diabetic progression.
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Affiliation(s)
- Yi-Han Zhou
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Lu-Ting Yu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, China
| | - Xiao-Nan Wang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - You-Jie Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Ke-Yi Xu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Xin Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Chun-Cheng Pu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Fei-Lu Xie
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Bing-Bing Xie
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yan Gao
- Institute of Suzhou Biobank, Suzhou Center for Disease Prevention and Control, Suzhou, China; Suzhou Institute of Advanced Study in Public Health, Gusu School, Nanjing Medical University, Suzhou, China.
| | - Chen Luo
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China; Antibody Engineering Laboratory, China Pharmaceutical University, Nanjing, China.
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Yu L, Zhou Y, Sun S, Wang R, Yu W, Xiao H, Yu Z, Luo C. Tumor-suppressive effect of Reg3A in COAD is mediated by T cell activation in nude mice. Biomed Pharmacother 2023; 169:115922. [PMID: 38011786 DOI: 10.1016/j.biopha.2023.115922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 11/14/2023] [Accepted: 11/20/2023] [Indexed: 11/29/2023] Open
Abstract
Regenerating family protein 3 A (Reg3A) is highly expressed in a variety of organs and inflammatory tissues, and is closely related to tumorigenesis and cancer progression. However, clinical statistics show that high expression of Reg3A is associated with better prognosis in colorectal cancer (CRC) patients, suggesting a tumor-suppressive effect. The precise action and underlying mechanism of Reg3A in CRC remain controversial. The present study sought to investigate the relationship among Reg3A expression, CRC development, and immune cell alteration in patients using the TCGA, GEPIA, PrognoScan, TIMER and TISIDB databases. Reg3A-overexpressing LoVo cell line (LoVo-Reg3A), a representative of colon adenocarcinoma (COAD), was constructed and the action of Reg3A was assessed in a xenograft nude mouse model. Our bioinformatical analyses revealed that Reg3A upregulation is highly associated with CRC, along with increased frequency of immune cell infiltration. In the xenograft nude mice, Reg3A overexpression offered a tumor-suppressive effect by inhibiting cell proliferation and promoting apoptosis. The result of RNA-seq suggested a positive regulation of leukocytes and an upregulation of T cells in LoVo-Reg3A tumor tissue. CD4+ and CD8+ T cells in tumors, splenic Reg3A-reactive IFN-γ+/CD4+ T cells, and serum TNF-α, IFN-γ and IL-17 were significantly increased by Reg3A overexpression. In the ex vivo co-culture experiment, elevated cytotoxic effect, increased proportion of CD3ε+ T cells, and upregulated expressions of TNF-α, IFN-γ and IL-17 were detected in the PBMCs isolated from LoVo-Reg3A cell-xenografted nude mice. In conclusion, high expression of Reg3A could activate and recruit T cells in COAD leading to the cytotoxic tumor-suppressive effect.
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Affiliation(s)
- Luting Yu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, China; School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Yihan Zhou
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Shaozheng Sun
- College of Science, Northeastern University, Boston, United States
| | - Runlin Wang
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Weihong Yu
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Hanyu Xiao
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Zhuxi Yu
- Department of critical care medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Chen Luo
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China; State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, China.
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Mir FA, Abdesselem HB, Cyprian F, Iskandarani A, Doudin A, Samra TA, Alkasem M, Abdalhakam I, Taheri S, Abou-Samra AB. Inflammatory protein signatures in individuals with obesity and metabolic syndrome. Sci Rep 2023; 13:22185. [PMID: 38092892 PMCID: PMC10719383 DOI: 10.1038/s41598-023-49643-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 12/10/2023] [Indexed: 12/17/2023] Open
Abstract
There is variability in the metabolic health status among individuals presenting with obesity; some may be metabolically healthy, while others may have developed the metabolic syndrome, a cluster including insulin resistance, hypertension, dyslipidemia, and increased risk of cardiovascular disease and type 2 diabetes. The mechanisms contributing to this metabolic heterogeneity are not fully understood. To address this question, plasma samples from 48 individuals with BMI ≥ 35 kg/m2 were examined (27 with and 21 without metabolic syndrome). Fasting plasma samples were subjected to Olink proteomics analysis for 184 cardiometabolic and inflammation-enriched proteins. Data analysis showed a clear differentiation between the two groups with distinct plasma protein expression profiles. Twenty-four proteins were differentially expressed (DEPs) between the two groups. Pathways related to immune cell migration, leukocyte chemotaxis, chemokine signaling, mucosal inflammatory response, tissue repair and remodeling were enriched in the group with metabolic syndrome. Functional analysis of DEPs revealed upregulation of 15 immunological pathways. The study identifies some of the pathways that are altered and reflect metabolic health in individuals with obesity. This provides valuable insights into some of the underlying mechanisms and can lead to identification of therapeutic targets to improve metabolic health in individuals with obesity.
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Affiliation(s)
- Fayaz Ahmad Mir
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, Qatar.
| | - Houari B Abdesselem
- Proteomics Core Facility, Office of the Vice President for Research (OVPR), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Farhan Cyprian
- College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ahmad Iskandarani
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, Qatar
| | - Asmma Doudin
- Laboratory of Immunoregulation, Research Department, Sidra Medicine, Doha, Qatar
| | - Tareq A Samra
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, Qatar
| | - Meis Alkasem
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, Qatar
| | - Ibrahem Abdalhakam
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, Qatar
| | - Shahrad Taheri
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, Qatar
- National Obesity Treatment Center, Hamad Medical Corporation, Doha, Qatar
- Weil Cornell Medicine -Qatar, Doha, Qatar
| | - Abdul-Badi Abou-Samra
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, Qatar
- National Obesity Treatment Center, Hamad Medical Corporation, Doha, Qatar
- Weil Cornell Medicine -Qatar, Doha, Qatar
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Yu L, Li L, Liu J, Sun H, Li X, Xiao H, Alfred MO, Wang M, Wu X, Gao Y, Luo C. Recombinant Reg3α Prevents Islet β-Cell Apoptosis and Promotes β-Cell Regeneration. Int J Mol Sci 2022; 23:ijms231810584. [PMID: 36142497 PMCID: PMC9504149 DOI: 10.3390/ijms231810584] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/05/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Progressive loss and dysfunction of islet β-cells has not yet been solved in the treatment of diabetes. Regenerating protein (Reg) has been identified as a trophic factor which is demonstrated to be associated with pancreatic tissue regeneration. We previously produced recombinant Reg3α protein (rReg3α) and proved that it protects against acute pancreatitis in mice. Whether rReg3α protects islet β-cells in diabetes has been elusive. In the present study, rReg3α stimulated MIN6 cell proliferation and resisted STZ-caused cell death. The protective effect of rReg3α was also found in mouse primary islets. In BALB/c mice, rReg3α administration largely alleviated STZ-induced diabetes by the preservation of β-cell mass. The protective mechanism could be attributed to Akt/Bcl-2/-xL activation and GRP78 upregulation. Scattered insulin-expressing cells and clusters with small size, low insulin density, and exocrine distribution were observed and considered to be neogenic. In isolated acinar cells with wheat germ agglutinin (WGA) labeling, rReg3α treatment generated insulin-producing cells through Stat3/Ngn3 signaling, but these cells were not fully functional in response to glucose stimulation. Our results demonstrated that rReg3α resists STZ-induced β-cell death and promotes β-cell regeneration. rReg3α could serve as a potential drug for β-cell maintenance in anti-diabetic treatment.
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Affiliation(s)
- Luting Yu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210037, China
| | - Liang Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Junli Liu
- MeDiC Program, The Research Institute of McGill University Health Centre, Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, QC H3A 0G4, Canada
| | - Hao Sun
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Xiang Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Hanyu Xiao
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Martin Omondi Alfred
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
- Institute of Primate Research, End of Karen Road, Karen, Nairobi P.O. Box 24481-00502, Kenya
| | - Min Wang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
- State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Xuri Wu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
- State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Yan Gao
- Institute of Suzhou Biobank, Suzhou Center for Disease Prevention and Control, Suzhou 215007, China
- Suzhou Institute of Advanced Study in Public Health, Gusu School, Nanjing Medical University, Suzhou 210029, China
- Correspondence: (Y.G.); (C.L.); Tel.: +86-0512-6826-2385 (Y.G.); +86-138-1388-3828 (C.L.)
| | - Chen Luo
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
- State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing 210009, China
- Correspondence: (Y.G.); (C.L.); Tel.: +86-0512-6826-2385 (Y.G.); +86-138-1388-3828 (C.L.)
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6
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Levetan C. Frederick Banting's observations leading to the potential for islet neogenesis without transplantation. J Diabetes 2022; 14:104-110. [PMID: 34967992 PMCID: PMC9060105 DOI: 10.1111/1753-0407.13246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/12/2021] [Accepted: 11/15/2021] [Indexed: 11/29/2022] Open
Abstract
On 31 October 1920, Sir Frederick Banting, while preparing for a medical student lecture on diabetes, a topic that he knew little about, learned how pancreatic stones resulted in the formation of new islets of Langerhans. He then scribbled down a potential research study of tying off the ducts of the pancreas and collecting the secretions to improve diabetes. These secretions became known as insulin. A century later, 60 different oral medications and 20 different insulins are available for the treatment of diabetes, yet none stimulate new islet formation. One hundred years later, after the discovery of insulin, more than a dozen research teams from around the world have demonstrated that similar studies to Banting's pancreatic ligation studies have resulted in upregulation of the REG gene. There are now more than 200 publications on the role of Reg gene proteins and shorter Reg peptides in initiating new islet formation islet from exocrine pancreatic ducts and protecting against inflammation to islets resulting in islet death. Human data through Phase 2b in both type 1 and 2 diabetes patients with diabetes for an average of 20 years have demonstrated that the use of a shorter bioactive Reg peptide can generate new endogenous insulin production, resulting in significant reductions in hemoglobin A1C and increases in stimulated C-peptide. The observations of Frederick Banting, one century ago, may now lead to the generation of therapeutics that form new islets without the need for transplantation.
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Affiliation(s)
- Claresa Levetan
- Fellow with Distinction, American College of Endocrinology, Diplomate, American Board of Internal Medicine, Diabetes, Endocrinology and MetabolismGrand View HealthLansdalePennsylvaniaUSA
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Cao Y, Tian Y, Liu Y, Su Z. Reg3β: A Potential Therapeutic Target for Tissue Injury and Inflammation-Associated Disorders. Int Rev Immunol 2021; 41:160-170. [PMID: 33426979 DOI: 10.1080/08830185.2020.1869731] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Since regenerating islet-derived 3β (Reg3β) was first reported, various studies have been conducted to explore the involvement of Reg3β in a gamut of maladies, such as diabetes, pancreatitis, pancreatic ductal adenocarcinoma, and extrapancreatic maladies such as inflammatory bowel disease, acute liver failure, and myocardial infarction. Surprisingly, there is currently no systematic review of Reg3β. Therefore, we summarize the structural characteristics, transcriptional regulation, putative receptors, and signaling pathways of Reg3β. The exact functional roles in various diseases, especially gastrointestinal and liver diseases, are also discussed. Reg3β plays multiple roles in promoting proliferation, inducing differentiation, preventing apoptosis, and resisting bacteria. The present review may provide new directions for the diagnosis and treatment of gastrointestinal, liver, and pancreatic diseases.
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Affiliation(s)
- Yuwen Cao
- International Genome Center, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu University, Zhenjiang, China
| | - Yu Tian
- International Genome Center, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu University, Zhenjiang, China
| | - Yueqin Liu
- Laboratory Center, the Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhaoliang Su
- International Genome Center, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu University, Zhenjiang, China.,Laboratory Center, the Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
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Sever D, Hershko-Moshe A, Srivastava R, Eldor R, Hibsher D, Keren-Shaul H, Amit I, Bertuzzi F, Krogvold L, Dahl-Jørgensen K, Ben-Dov IZ, Landsman L, Melloul D. NF-κB activity during pancreas development regulates adult β-cell mass by modulating neonatal β-cell proliferation and apoptosis. Cell Death Discov 2021; 7:2. [PMID: 33414444 PMCID: PMC7790827 DOI: 10.1038/s41420-020-00386-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/14/2020] [Accepted: 11/28/2020] [Indexed: 12/13/2022] Open
Abstract
NF-κB is a well-characterized transcription factor, widely known for its roles in inflammation and immune responses, as well as in control of cell division and apoptosis. However, its function in β-cells is still being debated, as it appears to depend on the timing and kinetics of its activation. To elucidate the temporal role of NF-κB in vivo, we have generated two transgenic mouse models, the ToIβ and NOD/ToIβ mice, in which NF-κB activation is specifically and conditionally inhibited in β-cells. In this study, we present a novel function of the canonical NF-κB pathway during murine islet β-cell development. Interestingly, inhibiting the NF-κB pathway in β-cells during embryogenesis, but not after birth, in both ToIβ and NOD/ToIβ mice, increased β-cell turnover, ultimately resulting in a reduced β-cell mass. On the NOD background, this was associated with a marked increase in insulitis and diabetes incidence. While a robust nuclear immunoreactivity of the NF-κB p65-subunit was found in neonatal β-cells, significant activation was not detected in β-cells of either adult NOD/ToIβ mice or in the pancreata of recently diagnosed adult T1D patients. Moreover, in NOD/ToIβ mice, inhibiting NF-κB post-weaning had no effect on the development of diabetes or β-cell dysfunction. In conclusion, our data point to NF-κB as an important component of the physiological regulatory circuit that controls the balance of β-cell proliferation and apoptosis in the early developmental stages of insulin-producing cells, thus modulating β-cell mass and the development of diabetes in the mouse model of T1D.
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Affiliation(s)
- Dror Sever
- Department of Endocrinology, Laboratory of Medical Transcriptomics, Nephrology Services, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.,University of Copenhagen, Novo Nordisk Foundation Center for Stem Cell Biology, DanStem. Faculty for Health and Medical Sciences, Blegdamsvej 3B. DK-2200, Copenhagen, Denmark
| | - Anat Hershko-Moshe
- Department of Endocrinology, Laboratory of Medical Transcriptomics, Nephrology Services, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
| | - Rohit Srivastava
- Department of Endocrinology, Laboratory of Medical Transcriptomics, Nephrology Services, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
| | - Roy Eldor
- Diabetes Unit, Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel.,The Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel
| | - Daniel Hibsher
- The Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel
| | - Hadas Keren-Shaul
- Department of Immunology, Weizmann Institute, Rehovot, 76100, Israel
| | - Ido Amit
- Department of Immunology, Weizmann Institute, Rehovot, 76100, Israel
| | - Federico Bertuzzi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
| | - Lars Krogvold
- Paediatric Department, Oslo University Hospital HF, P. O. Box, 4950, Nydalen, 0424, Oslo, Norway
| | - Knut Dahl-Jørgensen
- Paediatric Department, Oslo University Hospital HF, P. O. Box, 4950, Nydalen, 0424, Oslo, Norway
| | - Iddo Z Ben-Dov
- Laboratory of Medical Transcriptomics, Nephrology Services, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
| | - Limor Landsman
- The Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel
| | - Danielle Melloul
- Department of Endocrinology, Laboratory of Medical Transcriptomics, Nephrology Services, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
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9
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Hiraki D, Uehara O, Kuramitsu Y, Morikawa T, Harada F, Yoshida K, Akino K, Chiba I, Asaka M, Abiko Y. P. gingivalis Lipopolysaccharide Stimulates the Upregulated Expression of the Pancreatic Cancer-Related Genes Regenerating Islet-Derived 3 A/G in Mouse Pancreas. Int J Mol Sci 2020; 21:ijms21197351. [PMID: 33027970 PMCID: PMC7583020 DOI: 10.3390/ijms21197351] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/01/2020] [Accepted: 10/01/2020] [Indexed: 02/07/2023] Open
Abstract
Although epidemiological studies have shown a relationship between periodontal disease and pancreatic cancer, the molecular mechanisms involved remain unclear. In this study, the effects of systemic administration of Porphyromonas gingivalis lipopolysaccharide (PG-LPS) on gene expression were comprehensively explored in mouse pancreas that did not demonstrate any signs of inflammation. PG-LPS was prepared in physiological saline and intraperitoneally administered to male mice at a concentration of 5 mg/kg every 3 days for 1 month. After extracting total RNA from the excised mice pancreas, a comprehensive DNA microarray analysis of gene expression was performed. Tissue specimens were also subjected to hematoxylin-eosin staining and immunohistochemistry using anti-regenerating islet-derived 3A and G (Reg3A/G) antibody. ImageJ software was used to quantify the area of Reg3A/G positive cells in pancreatic islets by binarizing image date followed by area extraction. The results were compared using Mann-Whitney U test. Data are presented as mean ± standard deviation (SD) with p < 0.05 considered as significant. Reg3G, a gene related to pancreatic cancer, was one of the 10 genes with the highest levels of expression in the pancreas stimulated with PG-LPS. The comprehensive analysis revealed a 73-fold increase in Reg3G expression level in the PG-LPS group when compared with the control group; in addition, the expression level of Reg3A was increased by 11-fold in the PG-LPS group. Image analysis showed that the ratio of Reg3A/G positive cells was higher in the PG-LPS group than the control. Immunostaining showed the presence of Reg3A/G-positive cells in the alpha-cell equivalent areas around the islets of Langerhans in the PG-LPS group. These results support the notion that periodontal disease may be a risk factor for pancreatic cancer.
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Affiliation(s)
- Daichi Hiraki
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan;
| | - Osamu Uehara
- Division of Disease Control and Molecular Epidemiology, Department of Oral Growth and Development, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan; (O.U.); (I.C.)
| | - Yasuhiro Kuramitsu
- Research Institute of Cancer Prevention, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan; (Y.K.); (K.A.); (M.A.)
| | - Tetsuro Morikawa
- Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan; (T.M.); (K.Y.)
| | - Fumiya Harada
- Division of Oral and Maxillofacial Surgery, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan;
| | - Koki Yoshida
- Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan; (T.M.); (K.Y.)
| | - Kozo Akino
- Research Institute of Cancer Prevention, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan; (Y.K.); (K.A.); (M.A.)
| | - Itsuo Chiba
- Division of Disease Control and Molecular Epidemiology, Department of Oral Growth and Development, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan; (O.U.); (I.C.)
| | - Masahiro Asaka
- Research Institute of Cancer Prevention, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan; (Y.K.); (K.A.); (M.A.)
| | - Yoshihiro Abiko
- Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan; (T.M.); (K.Y.)
- Correspondence: ; Tel.: +81-133-23-1211
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10
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Haddadi MH, Hajizadeh-Saffar E, Khosravi-Maharlooei M, Basiri M, Negahdari B, Baharvand H. Autoimmunity as a target for chimeric immune receptor therapy: A new vision to therapeutic potential. Blood Rev 2020; 41:100645. [DOI: 10.1016/j.blre.2019.100645] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 11/12/2019] [Accepted: 11/22/2019] [Indexed: 12/25/2022]
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11
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Takagaki Y, Lee SM, Dongqing Z, Kitada M, Kanasaki K, Koya D. Endothelial autophagy deficiency induces IL6 - dependent endothelial mesenchymal transition and organ fibrosis. Autophagy 2020; 16:1905-1914. [PMID: 31965901 DOI: 10.1080/15548627.2020.1713641] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Macroautophagy/autophagy plays a vital role in the homeostasis of diverse cell types. Vascular endothelial cells contribute to vascular health and play a unique role in vascular biology. Here, we demonstrated that autophagy defects in endothelial cells induced IL6 (interleukin 6)-dependent endothelial-to-mesenchymal transition (EndMT) and organ fibrosis with metabolic defects in mice. Inhibition of autophagy, either by a specific inhibitor or small interfering RNA (siRNA) for ATG5 (autophagy related 5), in human microvascular endothelial cells (HMVECs) induced EndMT. The IL6 level was significantly higher in ATG5 siRNA-transfected HMVECs culture medium compared with the control HMVECs culture medium, and neutralization of IL6 by a specific antibody completely inhibited EndMT in ATG5 siRNA-transfected HMVECs. Similar to the in vitro data, endothelial-specific atg5 knockout mice (Atg5 Endo; Cdh5-Cre Atg5 flox/flox mice) displayed both EndMT-associated kidney and heart fibrosis when compared to littermate controls. The plasma level of IL6 was higher in Atg5 Endo compared to that of control mice, and fibrosis was accelerated in Atg5 Endo treated with a HFD; neutralization of IL6 by a specific antibody inhibited EndMT and fibrosis in HFD-fed Atg5 Endo associated with the amelioration of metabolic defects. These results revealed the essential role of autophagy in endothelial cell integrity and revealed that the disruption of endothelial autophagy could lead to significant pathological IL6-dependent EndMT and organ fibrosis. Abbreviations: 3-MA: 3-methyladenine; ATG5: autophagy related 5; EndMT: endothelial-to-mesenchymal transition; HES: hematoxylin and eosin stain; HFD: high-fat diet; HMVECs: human microvascular endothelial cells; IFNG: interferon gamma; IL6: interleukin 6; MTS: Masson's trichrome staining; NFD: normal-fat diet; siRNA: small interfering RNA; SMAD3: SMAD family member 3; TGFB: transforming growth factor β; TNF: tumor necrosis factor; VEGFA: vascular endothelial growth factor A.
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Affiliation(s)
- Yuta Takagaki
- Department of Diabetology and Endocrinology, Kanazawa Medical University , Uchinada, Japan
| | - Seon Myeong Lee
- Department of Diabetology and Endocrinology, Kanazawa Medical University , Uchinada, Japan
| | - Zha Dongqing
- Department of Diabetology and Endocrinology, Kanazawa Medical University , Uchinada, Japan
| | - Munehiro Kitada
- Department of Diabetology and Endocrinology, Kanazawa Medical University , Uchinada, Japan.,Division of Anticipatory Molecular Food Science and Technology, Kanazawa Medical University , Uchinada, Japan
| | - Keizo Kanasaki
- Department of Diabetology and Endocrinology, Kanazawa Medical University , Uchinada, Japan.,Division of Anticipatory Molecular Food Science and Technology, Kanazawa Medical University , Uchinada, Japan.,Internal Medicine 1, Shimane University Faculty of Medicine , Izumo, Japan
| | - Daisuke Koya
- Department of Diabetology and Endocrinology, Kanazawa Medical University , Uchinada, Japan.,Division of Anticipatory Molecular Food Science and Technology, Kanazawa Medical University , Uchinada, Japan
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12
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Chen Z, Downing S, Tzanakakis ES. Four Decades After the Discovery of Regenerating Islet-Derived (Reg) Proteins: Current Understanding and Challenges. Front Cell Dev Biol 2019; 7:235. [PMID: 31696115 PMCID: PMC6817481 DOI: 10.3389/fcell.2019.00235] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 09/30/2019] [Indexed: 12/15/2022] Open
Abstract
Regenerating islet-derived (Reg) proteins have emerged as multifunctional agents with pro-proliferative, anti-apoptotic, differentiation-inducing and bactericidal properties. Over the last 40 years since first discovered, Reg proteins have been implicated in a gamut of maladies including diabetes, various types of cancer of the digestive tract, and Alzheimer disease. Surprisingly though, a consensus is still absent on the regulation of their expression, and molecular underpinning of their function. Here, we provide a critical appraisal of recent findings in the field of Reg protein biology. Specifically, the structural characteristics are reviewed particularly in connection with established or purported functions of different members of the Reg family. Moreover, Reg expression patterns in different tissues both under normal and pathophysiological conditions are summarized. Putative receptors and cascades reported to relay Reg signaling inciting cellular responses are presented aiming at a better appreciation of the biological activities of the distinct Reg moieties. Challenges are also discussed that have hampered thus far the rapid progress in this field such as the use of non-standard nomenclature for Reg molecules among various research groups, the existence of multiple Reg members with significant degree of homology and possibly compensatory modes of action, and the need for common assays with robust readouts of Reg activity. Coordinated research is warranted going forward, given that several research groups have independently linked Reg proteins to diseased states and raised the possibility that these biomolecules can serve as therapeutic targets and biomarkers.
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Affiliation(s)
- Zijing Chen
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, United States
| | - Shawna Downing
- Clinical and Translational Science Institute, Tufts Medical Center, Boston, MA, United States
| | - Emmanuel S Tzanakakis
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, United States.,Clinical and Translational Science Institute, Tufts Medical Center, Boston, MA, United States
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13
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Kaddour N, Zhang D, Gao ZH, Liu JL. Recombinant protein CCN5/WISP2 promotes islet cell proliferation and survival in vitro. Growth Factors 2019; 37:120-130. [PMID: 31437074 DOI: 10.1080/08977194.2019.1652400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Pancreatic ß cell proliferation, survival and function are key elements that need to be considered in developing novel antidiabetic therapies. We recently identified CCN5/WISP2 to have potential growth promoting properties when overexpressed in ß cells; however, further investigations are needed to validate those properties. In this study, we demonstrated that exogenous treatment of insulinoma cells and primary islets with recombinant CCN5 (rh-CCN5) protein enhanced the proliferative capacity which was correlated with activation of cell-cycle regulators CDK4 and cyclin D1. Furthermore, pre-incubation of these cells with rh-CCN5 enhanced their survival rate after being exposed to harsh treatments such as streptozotocin and high concentrations of glucose and free fatty acids. CCN5 as well caused an upregulation in the expression of key genes associated with ß cell identity and function such as GLUT-2 and GCK. Finally, CCN5 activated FAK and downstream ERK kinases which are known to stimulate cell proliferation and survival. Hence, our results validate the growth promoting activities of rh-CCN5 in ß cells and open the door for further investigations in vivo.
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Affiliation(s)
- Nancy Kaddour
- Frasers Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, Canada
| | - Di Zhang
- Frasers Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, Canada
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Zu-Hua Gao
- Department of Pathology, McGill University Health Centre, Montreal, Canada
| | - Jun-Li Liu
- Frasers Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, Canada
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14
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Yu L, Li X, Zhang Z, Du P, Liu JL, Li Y, Yin T, Yu W, Sun H, Wang M, Luo C. Dimorphic autoantigenic and protective effects of Reg2 peptide in the treatment of diabetic β-cell loss. Diabetes Obes Metab 2019; 21:1209-1222. [PMID: 30690849 DOI: 10.1111/dom.13644] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/18/2019] [Accepted: 01/24/2019] [Indexed: 12/26/2022]
Abstract
AIMS The potential effect of regenerating (Reg) proteins in the treatment of diabetes has been indicated in the past decade, but the clinical use of Reg proteins requires more advances in translational medicine. In the present study, we produced recombinant regenerating protein 2 (rReg2), to prove its protective effect against streptozocin (STZ)-induced diabetes in BALB/c mice. MATERIALS AND METHODS rReg2 was administrated in STZ-induced diabetic mice. Blood glucose, body weight, serum insulin and islet β-cell loss were determined. However, Reg2 has also been reported to serve as an autoantigen that induces autoimmune attacks on islets and aggravates diabetic development in non-obese diabetic mice. To address this contradiction, complete Freund's adjuvant was injected to generate a model that was hypersensitive to Reg2. In this model, islet CD8 T-cell infiltration, serum Reg2 antibody and interleukin (IL)-4 and IL-10, and splenic CD4+/interferon (IFN)-γ+ T cells were determined. RESULTS Direct rReg2 pretreatment preserved islet β-cell mass against STZ and improved glycaemia, body weight and serum insulin content. The protection against cell death was further confirmed in cultured mouse islets and MIN6 cells. On the other hand, significant elevations of serum Reg2 antibody and splenic CD4+/IFN-γ+ T cells, and decreases in serum IL-4 and IL-10 were detected in rReg2-vaccinated mice, which may contribute to the accelerated diabetes. Interestingly, these mice, upon further rReg2 treatment, exhibited alleviated diabetic conditions with less islet CD8+ T-cell infiltration. CONCLUSION rReg2 treatment ameliorated STZ-induced diabetes in normal BALB/c mice. By contrast, rReg2 vaccination exacerbated, but further rReg2 treatment alleviated, the severity of STZ-induced diabetes. Thus, the protective effect of rReg2 is predominant over the autoantigenic β-cell destruction, supporting the potential of rReg2 in the clinical treatment of diabetes.
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Affiliation(s)
- Luting Yu
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
- Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, Canada
| | - Xiang Li
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Zhiyuan Zhang
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Pei Du
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Jun-Li Liu
- Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, Canada
| | - Youjie Li
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Tianqi Yin
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Weihong Yu
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Hao Sun
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Min Wang
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
- State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, China
| | - Chen Luo
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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15
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Jayasimhan A, Ellis DP, Ziegler AI, Slattery RM. Pancreatic ductal cell antigens are important in the development of invasive insulitis in Non-Obese Diabetic mice. J Neuroimmunol 2019; 327:1-9. [PMID: 30685070 DOI: 10.1016/j.jneuroim.2019.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 01/01/2019] [Accepted: 01/02/2019] [Indexed: 01/12/2023]
Abstract
Type 1 Diabetes (T1D) is an autoimmune disease in which insulin producing beta cells of the pancreas are selectively destroyed. Glial Fibrillary Acidic Protein (GFAP) expressed in peri-islet Schwann cells (pSCs) and in the ductal cells of the pancreas is one of the candidate autoantigens for T1D. Immune responses to GFAP expressing cell types precede the islet autoimmunity in Non-Obese Diabetic (NOD) mice. By removing MHC class I from GFAP expressing cell types, we tested the role of autoantigens presented by these cell types in the development of invasive insulitis. Our findings indicate that antigens expressed by pancreatic ductal cells are important in the development of invasive insulitis in NOD mice.
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Affiliation(s)
- Abhirup Jayasimhan
- Department of Immunology and Pathology, Monash University, Melbourne, Australia.
| | - Darcy P Ellis
- Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
| | - Alexandra I Ziegler
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
| | - Robyn M Slattery
- Department of Immunology and Pathology, Monash University, Melbourne, Australia
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16
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Vahdat S. The complex effects of adipokines in the patients with kidney disease. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2018; 23:60. [PMID: 30181742 PMCID: PMC6091131 DOI: 10.4103/jrms.jrms_1115_17] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 03/12/2018] [Accepted: 04/29/2018] [Indexed: 12/27/2022]
Abstract
Kidney diseases are categorized as the highest prevalent ones with worldwide noticeable incidence. They cause accelerated cardiovascular diseases and noticeable mortalities. Adipose tissue and its messengers, adipokines, are reported to have the highest relationship with end-stage renal diseases or chronic kidney diseases. Over recent years, with shifting of scientists’ mindset from a simple overview of adipose tissue as a fat store to the complex paradigm of this issue as a multipotential secretory organ, the importance of studies on this tissue has emerged.
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Affiliation(s)
- Sahar Vahdat
- Isfahan Kidney Diseases Research Center, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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17
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Su H, Lei CT, Zhang C. Interleukin-6 Signaling Pathway and Its Role in Kidney Disease: An Update. Front Immunol 2017; 8:405. [PMID: 28484449 PMCID: PMC5399081 DOI: 10.3389/fimmu.2017.00405] [Citation(s) in RCA: 355] [Impact Index Per Article: 44.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 03/22/2017] [Indexed: 12/19/2022] Open
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine that not only regulates the immune and inflammatory response but also affects hematopoiesis, metabolism, and organ development. IL-6 can simultaneously elicit distinct or even contradictory physiopathological processes, which is likely discriminated by the cascades of signaling pathway, termed classic and trans-signaling. Besides playing several important physiological roles, dysregulated IL-6 has been demonstrated to underlie a number of autoimmune and inflammatory diseases, metabolic abnormalities, and malignancies. This review provides an overview of basic concept of IL-6 signaling pathway as well as the interplay between IL-6 and renal-resident cells, including podocytes, mesangial cells, endothelial cells, and tubular epithelial cells. Additionally, we summarize the roles of IL-6 in several renal diseases, such as IgA nephropathy, lupus nephritis, diabetic nephropathy, acute kidney injury, and chronic kidney disease.
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Affiliation(s)
- Hua Su
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun-Tao Lei
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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18
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Luo C, Yu LT, Yang MQ, Li X, Zhang ZY, Alfred MO, Liu JL, Wang M. Recombinant Reg3β protein protects against streptozotocin-induced β-cell damage and diabetes. Sci Rep 2016; 6:35640. [PMID: 27767186 PMCID: PMC5073304 DOI: 10.1038/srep35640] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 10/03/2016] [Indexed: 12/11/2022] Open
Abstract
Regenerating genes (Reg) have been found during the search for factors involved in pancreatic islet regeneration. Our recent study discovered that pancreatic β-cell-specific overexpression of Reg3β protects against streptozotocin (Stz) -induced diabetes in mice. To investigate its potential roles in the treatment of diabetes, we produced a recombinant Reg3β protein and provided evidence that it is active in promoting islet β-cell survival against Stz- triggered cell death. Though ineffective in alleviating preexisting diabetes, pretreatment of recombinant Reg3β was capable of minimizing the Stz-induced hyperglycemia and weight loss, by preserving serum and pancreatic insulin levels, and islet β-cell mass. No obvious changes were observed in the rate of cell proliferation and hypertrophy in α- or acinar-cells after treatment with recombinant Reg3β. The underlying mechanism of Reg3β-mediated protection seems to involve Akt activation which upregulates Bcl-2 and Bcl-xL levels and consequently promotes cell survival.
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Affiliation(s)
- Chen Luo
- School of Life Science &Technology, China Pharmaceutical University, Nanjing, China.,State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, China
| | - Lu-Ting Yu
- School of Life Science &Technology, China Pharmaceutical University, Nanjing, China
| | - Meng-Qi Yang
- School of Life Science &Technology, China Pharmaceutical University, Nanjing, China
| | - Xiang Li
- School of Life Science &Technology, China Pharmaceutical University, Nanjing, China
| | - Zhi-Yuan Zhang
- School of Life Science &Technology, China Pharmaceutical University, Nanjing, China
| | - Martin O Alfred
- School of Life Science &Technology, China Pharmaceutical University, Nanjing, China
| | - Jun-Li Liu
- Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, Canada
| | - Min Wang
- School of Life Science &Technology, China Pharmaceutical University, Nanjing, China.,State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, China
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19
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Bianchi MS, Bianchi S, Hernado-Insúa A, Martinez LM, Lago N, Libertun C, Chasseing NA, Montaner AD, Lux-Lantos VA. Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes. Am J Physiol Endocrinol Metab 2016; 311:E380-95. [PMID: 27329801 DOI: 10.1152/ajpendo.00104.2016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 06/07/2016] [Indexed: 12/17/2022]
Abstract
Type 1 diabetes (T1D) originates from autoimmune β-cell destruction. IMT504 is an immunomodulatory oligonucleotide that increases mesenchymal stem cell cloning capacity and reverts toxic diabetes in rats. Here, we evaluated long-term (20 doses) and short-term (2-6 doses) effects of IMT504 (20 mg·kg(-1)·day(-1) sc) in an immunodependent diabetes model: multiple low-dose streptozotocin-injected BALB/c mice (40 mg·kg(-1)·day(-1) ip for 5 consecutive days). We determined blood glucose, glucose tolerance, serum insulin, islet morphology, islet infiltration, serum cytokines, progenitor cell markers, immunomodulatory proteins, proliferation, apoptosis, and islet gene expression. IMT504 reduced glycemia, induced β-cell recovery, and impaired islet infiltration. IMT504 induced early blood glucose decrease and infiltration inhibition, increased β-cell proliferation and decreased apoptosis, increased islet indoleamine 2,3-dioxygenase (IDO) expression, and increased serum tumor necrosis factor and interleukin-6 (IL-6). IMT504 affected islet gene expression; preproinsulin-2, proglucagon, somatostatin, nestin, regenerating gene-1, and C-X-C motif ligand-1 cytokine (Cxcl1) increased in islets from diabetic mice and were decreased by IMT504. IMT504 downregulated platelet endothelial cell adhesion molecule-1 (Pecam1) in islets from control and diabetic mice, whereas it increased regenerating gene-2 (Reg2) in islets of diabetic mice. The IMT504-induced increase in IL-6 and islet IDO expression and decreased islet Pecam1 and Cxcl1 mRNA expression could participate in keeping leukocyte infiltration at bay, whereas upregulation of Reg2 may mediate β-cell regeneration. We conclude that IMT504 effectively reversed immunodependent diabetes in mice. Corroboration of these effects in a model of autoimmune diabetes more similar to human T1D could provide promising results for the treatment of this disease.
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MESH Headings
- Animals
- Apoptosis/drug effects
- Blood Glucose/drug effects
- Blood Glucose/metabolism
- Cell Proliferation/drug effects
- Chemokine CXCL1/drug effects
- Chemokine CXCL1/genetics
- Cytokines/drug effects
- Cytokines/metabolism
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/metabolism
- Disease Models, Animal
- Glucose Tolerance Test
- Indoleamine-Pyrrole 2,3,-Dioxygenase/drug effects
- Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
- Insulin/genetics
- Insulin/metabolism
- Insulin-Secreting Cells/drug effects
- Insulin-Secreting Cells/metabolism
- Interleukin-6/metabolism
- Islets of Langerhans/drug effects
- Islets of Langerhans/metabolism
- Islets of Langerhans/pathology
- Lithostathine/drug effects
- Lithostathine/genetics
- Male
- Mice
- Mice, Inbred BALB C
- Nestin/drug effects
- Nestin/genetics
- Oligodeoxyribonucleotides/pharmacology
- Pancreatitis-Associated Proteins
- Platelet Endothelial Cell Adhesion Molecule-1/drug effects
- Platelet Endothelial Cell Adhesion Molecule-1/genetics
- Proglucagon/drug effects
- Proglucagon/genetics
- Protein Precursors/drug effects
- Protein Precursors/genetics
- Proteins/drug effects
- Proteins/genetics
- RNA, Messenger/drug effects
- RNA, Messenger/metabolism
- Somatostatin/drug effects
- Somatostatin/genetics
- Stem Cells/drug effects
- Stem Cells/metabolism
- Transcriptome/drug effects
- Tumor Necrosis Factor-alpha/drug effects
- Tumor Necrosis Factor-alpha/metabolism
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Affiliation(s)
- María S Bianchi
- Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Stefanía Bianchi
- Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | | | - Leandro M Martinez
- Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Néstor Lago
- Facultad de Medicina, Universidad de Buenos Aires. Buenos Aires, Argentina
| | - Carlos Libertun
- Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina; Facultad de Medicina, Universidad de Buenos Aires. Buenos Aires, Argentina
| | - Norma A Chasseing
- Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | | | - Victoria A Lux-Lantos
- Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina;
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20
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Ding Y, Xu Y, Shuai X, Shi X, Chen X, Huang W, Liu Y, Liang X, Zhang Z, Su D. Reg3α Overexpression Protects Pancreatic β Cells from Cytokine-Induced Damage and Improves Islet Transplant Outcome. Mol Med 2015; 20:548-558. [PMID: 25826674 DOI: 10.2119/molmed.2014.00104] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 12/16/2014] [Indexed: 01/12/2023] Open
Abstract
The process of islet transplantation for treating type 1 diabetes has been limited by the high level of graft failure. This may be overcome by locally delivering trophic factors to enhance engraftment. Regenerating islet-derived protein 3α (Reg3α) is a pancreatic secretory protein which functions as an antimicrobial peptide in control of inflammation and cell proliferation. In this study, to investigate whether Reg3α could improve islet engraftment, a marginal mass of syngeneic islets pretransduced with adenoviruses expressing Reg3α or control EGFP were transplanted under the renal capsule of streptozotocin-induced diabetic mice. Mice receiving islets with elevated Reg3α production exhibited significantly lower blood glucose levels (9.057 ± 0.59 mmol/L versus 13.48 ± 0.35 mmol/L, P < 0.05) and improved glucose-stimulated insulin secretion (1.80 ± 0.17 ng/mL versus 1.16 ± 0.16 ng/mL, P < 0.05) compared with the control group. The decline of apoptotic events (0.57% ± 0.15% versus 1.06% ± 0.07%, P < 0.05) and increased β-cell proliferation (0.70% ± 0.10% versus 0.36% ± 0.14%, P < 0.05) were confirmed in islet grafts overexpressing Reg3α by morphometric analysis. Further experiments showed that Reg3α production dramatically protected cultured islets and pancreatic β cells from cytokine-induced apoptosis and the impairment of glucose-stimulated insulin secretion. Moreover, exposure to cytokines led to the activation of MAPKs in pancreatic β cells, which was reversed by Reg3α overexpression in contrast to control group. These results strongly suggest that Reg3α could enhance islet engraftments through its cytoprotective effect and advance the therapeutic efficacy of islet transplantation.
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Affiliation(s)
- Ying Ding
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Yuemei Xu
- Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Xuanyu Shuai
- Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Xuhui Shi
- Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Xiang Chen
- Center of Cellular Therapy, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wenbin Huang
- Department of Pathology, Nanjing First Hospital, Nanjing, China
| | - Yun Liu
- Center of Metabolic Research, Nanjing Medical University, Nanjing, China
| | - Xiubin Liang
- Center of Metabolic Research, Nanjing Medical University, Nanjing, China
| | - Zhihong Zhang
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, China.,Center of Cellular Therapy, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Center of Metabolic Research, Nanjing Medical University, Nanjing, China
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21
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Uppal SS, Naveed AK, Baig S, Chaudhry B. Expression of REG Iα gene in type 2 diabetics in Pakistan. Diabetol Metab Syndr 2015; 7:96. [PMID: 26568772 PMCID: PMC4643495 DOI: 10.1186/s13098-015-0092-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 11/02/2015] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The escalating rate of diabetes' has prompted researchers around the world to explore for early markers. A deficit of functional β-cell mass plays a central role in the pathophysiology of type 2 diabetes. The REG (Regenerating) gene, encoding a 166 amino acid REG protein was discovered in rats and humans which is released in response to β-cells damage and play a role in their regeneration. The objective of this study was to characterize serum levels of REG Iα proteins in type 2 diabetic patients as indicator of β-cell apoptosis as well as regeneration. METHODS Unrelated type 2 diabetic patients (n = 55) of different age groups and disease duration were recruited from the Medical OPD of PNS Shifa Hospital. Age and sex matched non diabetic controls (n = 20) without family history of diabetes were selected from the same setting. Demographical details were recorded on a structured questionnaire. Biochemical parameters like FBG, HbA1c, TC and TG levels were measured. Serum levels of REG Iα protein were determined by ELISA. RESULTS Levels of REG Iα protein were found significantly raised in type 2 diabetic patients compared to controls (p < 001). Patients with short duration of the disease had higher levels of REG Iα as compared to patients with longer duration of the disease. Although the patients were on anti hyperglycemic agents, a positive correlation was found between REG Iα serum levels, FBG and HbA1c levels. Patients with higher BMI had higher levels of serum REG Iα levels. Serum TC, TG and Hb levels showed no correlation. CONCLUSION REG Iα may be used as a marker/predictor of type 2 diabetes especially in the early stages of the disease.
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Affiliation(s)
- Sadaf Saleem Uppal
- />Department of Biochemistry and Molecular Biology, Army Medical College, Rawalpindi and National University of Science and Technology, Islamabad, Pakistan
| | - Abdul Khaliq Naveed
- />Department of Biochemistry, Islamic International Medical College, Riphah International University, Islamabad, Pakistan
| | - Saeeda Baig
- />Department of Biochemistry, Ziauddin University, Karachi, Pakistan
| | - Bushra Chaudhry
- />Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
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22
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Nayak DK, Calderon B, Vomund AN, Unanue ER. ZnT8-reactive T cells are weakly pathogenic in NOD mice but can participate in diabetes under inflammatory conditions. Diabetes 2014; 63:3438-48. [PMID: 24812429 PMCID: PMC4171664 DOI: 10.2337/db13-1882] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Autoantibodies to the islet-specific Zn transporter ZnT8 (Slc30a8), as well as CD4 T cells, have been identified in patients with type 1 diabetes. Here we examined for CD4 T-cell reactivity to ZnT8 epitopes in the NOD mouse. Immunization with a cytoplasmic domain of the protein or with peptides predicted to bind to I-A(g7) resulted in a CD4 T-cell response, indicating a lack of deletional tolerance. However, presentation by intraislet antigen-presenting cells (APC) to the T cells was not detectable in prediabetic mice. Presentation by islet APC was found only in islets of mice with active diabetes. In accordance, a culture assay indicated the weak transfer of ZnT8 reactivity from insulinomas or primary β-cells to APC for presentation to T cells. A T cell directed to one peptide (345-359) resulted in the transfer of diabetes, but only in conditions in which the recipient NOD mice or NOD.Rag1(-/-) mice were subjected to light irradiation. In late diabetic NOD mice, CD4 T cells were found as well as a weak antibody response. We conclude that in NOD mice, ZnT8 is a minor diabetogenic antigen that can participate in diabetes in conditions in which the islet is first made receptive to immunological insults.
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Affiliation(s)
- Deepak K Nayak
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Boris Calderon
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Anthony N Vomund
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Emil R Unanue
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
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23
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Beumer W, Welzen-Coppens JMC, van Helden-Meeuwsen CG, Gibney SM, Drexhage HA, Versnel MA. The gene expression profile of CD11c+ CD8α- dendritic cells in the pre-diabetic pancreas of the NOD mouse. PLoS One 2014; 9:e103404. [PMID: 25166904 PMCID: PMC4148310 DOI: 10.1371/journal.pone.0103404] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 07/01/2014] [Indexed: 11/19/2022] Open
Abstract
Two major dendritic cell (DC) subsets have been described in the pancreas of mice: The CD11c+ CD8α- DCs (strong CD4+ T cell proliferation inducers) and the CD8α+ CD103+ DCs (T cell apoptosis inducers). Here we analyzed the larger subset of CD11c+ CD8α- DCs isolated from the pancreas of pre-diabetic NOD mice for genome-wide gene expression (validated by Q-PCR) to elucidate abnormalities in underlying gene expression networks. CD11c+ CD8α- DCs were isolated from 5 week old NOD and control C57BL/6 pancreas. The steady state pancreatic NOD CD11c+ CD8α- DCs showed a reduced expression of several gene networks important for the prime functions of these cells, i.e. for cell renewal, immune tolerance induction, migration and for the provision of growth factors including those for beta cell regeneration. A functional in vivo BrdU incorporation test showed the reduced proliferation of steady state pancreatic DC. The reduced expression of tolerance induction genes (CD200R, CCR5 and CD24) was supported on the protein level by flow cytometry. Also previously published functional tests on maturation, immune stimulation and migration confirm the molecular deficits of NOD steady state DC. Despite these deficiencies NOD pancreas CD11c+ CD8α- DCs showed a hyperreactivity to LPS, which resulted in an enhanced pro-inflammatory state characterized by a gene profile of an enhanced expression of a number of classical inflammatory cytokines. The enhanced up-regulation of inflammatory genes was supported by the in vitro cytokine production profile of the DCs. In conclusion, our data show that NOD pancreatic CD11c+ CD8α- DCs show various deficiencies in steady state, while hyperreactive when encountering a danger signal such as LPS.
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Affiliation(s)
- Wouter Beumer
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | | | | | - Sinead M. Gibney
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Hemmo A. Drexhage
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- * E-mail:
| | - Marjan A. Versnel
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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24
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Aida K, Saitoh S, Nishida Y, Yokota S, Ohno S, Mao X, Akiyama D, Tanaka S, Awata T, Shimada A, Oikawa Y, Shimura H, Furuya F, Takizawa S, Ichijo M, Ichijo S, Itakura J, Fujii H, Hashiguchi A, Takasawa S, Endo T, Kobayashi T. Distinct cell clusters touching islet cells induce islet cell replication in association with over-expression of Regenerating Gene (REG) protein in fulminant type 1 diabetes. PLoS One 2014; 9:e95110. [PMID: 24759849 PMCID: PMC3997392 DOI: 10.1371/journal.pone.0095110] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 03/23/2014] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs), extracellular matrix (ECM), and possible cell clusters, are unclear. PROCEDURES The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans. RESULT Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG) Iα protein. The vesicles containing REG Iα protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG Iα protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells. CONCLUSION The acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG Iα protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG Iα in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells.
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Affiliation(s)
- Kaoru Aida
- Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Sei Saitoh
- Department of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Yoriko Nishida
- Department of Nursing, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Sadanori Yokota
- Section of Functional Morphology, Faculty of Pharmaceutical Sciences, Nagasaki International University, Saseho, Nagasaki, Japan
| | - Shinichi Ohno
- Department of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Xiayang Mao
- Department of Computer Science, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Daiichiro Akiyama
- Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Shoichiro Tanaka
- Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Takuya Awata
- Division of Endocrinology and Diabetes, Department of Medicine, Saitama Medical School, Moroyama, Saitama, Japan
| | - Akira Shimada
- Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan
| | - Youichi Oikawa
- Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan
| | - Hiroki Shimura
- Department of Laboratory Medicine, Fukushima Medical University, Fukushima, Fukushima, Japan
| | - Fumihiko Furuya
- Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Soichi Takizawa
- Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Masashi Ichijo
- Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Sayaka Ichijo
- Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Jun Itakura
- Department of Surgery I, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Hideki Fujii
- Department of Surgery I, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Akinori Hashiguchi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Shin Takasawa
- Department of Biochemistry, Nara Medical University, Kashihara, Wakayama, Japan
| | - Toyoshi Endo
- Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Tetsuro Kobayashi
- Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
- * E-mail:
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25
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Abstract
This paper reviews the presentation of peptides by major histocompatibility complex (MHC) class II molecules in the autoimmune diabetes of the nonobese diabetic (NOD) mouse. Islets of Langerhans contain antigen-presenting cells that capture the proteins and peptides of the beta cells' secretory granules. Peptides bound to I-A(g7), the unique MHC class II molecule of NOD mice, are presented in islets and in pancreatic lymph nodes. The various beta cell-derived peptides interact with selected CD4 T cells to cause inflammation and beta cell demise. Many autoreactive T cells are found in NOD mice, but not all have a major role in the initiation of the autoimmune process. I emphasize here the evidence pointing to insulin autoreactivity as a seminal component in the diabetogenic process.
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Affiliation(s)
- Emil R Unanue
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110;
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26
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Pancreatic β cell proliferation by intermittent hypoxia via up-regulation of Reg family genes and HGF gene. Life Sci 2013; 93:664-72. [DOI: 10.1016/j.lfs.2013.09.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 07/30/2013] [Accepted: 09/05/2013] [Indexed: 11/19/2022]
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27
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Gurr W, Shaw M, Herzog RI, Li Y, Sherwin R. Vaccination with single chain antigen receptors for islet-derived peptides presented on I-A(g7) delays diabetes in NOD mice by inducing anergy in self-reactiveT-cells. PLoS One 2013; 8:e69464. [PMID: 23894487 PMCID: PMC3722102 DOI: 10.1371/journal.pone.0069464] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2012] [Accepted: 06/10/2013] [Indexed: 11/19/2022] Open
Abstract
To develop a vaccination approach for prevention of type 1 diabetes (T1D) that selectively attenuates self-reactive T-cells targeting specific autoantigens, we selected phage-displayed single chain antigen receptor libraries for clones binding to a complex of the NOD classII MHC I-A(g7) and epitopes derived from the islet autoantigen RegII. Libraries were generated from B-cell receptor repertoires of classII-mismatched mice immunized with RegII-pulsed NOD antigen presenting cells or from T-cell receptor repertoires in pancreatic lymph nodes of NOD mice. Both approaches yielded clones recognizing a RegII-derived epitope in the context of I-A(g7), which activated autoreactive CD4(+) T-cells. A receptor with different specificity was obtained by converting the BDC2.5 TCR into single chain form. B- but not T-cells from donors vaccinated with the clones transferred protection from diabetes to NOD-SCID recipients if the specificity of the diabetes inducer cell and the single chain receptor were matched. B-cells and antibodies from donors vaccinated with the BDC2.5 single chain receptor induced a state of profound anergy in T-cells of BDC2.5 TCR transgenic NOD recipients while B-cells from donors vaccinated with a single chain receptor specific for I-A(g7) RegII peptide complexes induced only partial non-responsiveness. Vaccination of normal NOD mice with receptors recognizing I-A(g7) RegII peptide complexes or with the BDC2.5 single chain receptor delayed onset of T1D. Thus anti-idiotypic vaccination can be successfully applied to T1D with vaccines either generated from self-reactive T-cell clones or derived from antigen receptor libraries.
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Affiliation(s)
- Werner Gurr
- Department of Internal Medicine, Yale University, School of Medicine, New Haven, Connecticut, United States of America.
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28
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Abstract
Celiac disease (CD) is an autoimmune disorder, which damages the small intestine and is caused by ingestion of gluten in genetically susceptible individuals. The only known effective treatment is a lifelong gluten-free diet. Genetic risk factors have been identified and nearly all patients are HLA-DQ2 and/or HLA-DQ8 positive. Specific autoantibodies, IgA antitissue transglutaminase-2, antiendomysium, and antideaminated forms of gliadin peptide antibodies, are widely used as diagnostic aids in celiac patients. However, the discovery of new biomarkers may help in the diagnosis and follow-up of the disease. Recently, the molecule REG Iα, involved in tissue regeneration, has been proposed as a new biomarker of CD. REG Iα expression is increased in the target tissue and in the sera of celiac patients during damage and inflammation, decreasing after gluten-free diet. In this article we review the main biomarkers for diagnosis and monitoring of CD, focusing on the immune response-related mechanisms.
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29
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Luo C, Li B, Liu L, Yin HP, Wang M, Liu JL. Transcriptional activation of Reg2 and Reg3β genes by glucocorticoids and interleukin-6 in pancreatic acinar and islet cells. Mol Cell Endocrinol 2013; 365:187-96. [PMID: 23147030 DOI: 10.1016/j.mce.2012.10.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Revised: 09/21/2012] [Accepted: 10/18/2012] [Indexed: 12/27/2022]
Abstract
Reg family proteins are expressed in the pancreas and involved in pancreatitis and islet β-cell growth. In order to explore transcriptional control, we transfected luciferase reporter genes driven by Reg promoters into acinar AR42J and islet MIN6 cells. Dexamethasone (DEX) significantly increased the promoter expression of Reg2 and Reg3β genes and the levels of endogenous Reg3β mRNA and protein in AR42J cells. DEX-induced promoter activation was inhibited by the inhibitor of poly(ADP-ribose) polymerase, nicotinamide. In MIN6 cells, DEX moderately stimulated the transcription of Reg3β but not Reg2 promoter. While IL-6 alone had no effect, coculture with DEX produced a remarkable synergism on Reg3β gene transcription, which was abolished by nicotinamide. Our results demonstrated a significant and direct stimulation of Reg2 and Reg3β genes by glucocorticoids, all three were activated in response to inflammation such as in pancreatitis. Prominent stimulation of specific Reg genes by glucocorticoids may constitute a functional synergism.
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Affiliation(s)
- Chen Luo
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China; Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, Canada
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30
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Parikh A, Stephan AF, Tzanakakis ES. Regenerating proteins and their expression, regulation and signaling. Biomol Concepts 2011; 3:57-70. [PMID: 22582090 DOI: 10.1515/bmc.2011.055] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The regenerating (Reg) protein family comprises C-type lectin-like proteins discovered independently during pancreatitis and pancreatic islet regeneration. However, an increasing number of studies provide evidence of participation of Reg proteins in the proliferation and differentiation of diverse cell types. Moreover, Reg family members are associated with various pathologies, including diabetes and forms of gastrointestinal cancer. These findings have led to the emergence of key roles for Reg proteins as anti-inflammatory, antiapoptotic and mitogenic agents in multiple physiologic and disease contexts. Yet, there are significant gaps in our knowledge regarding the regulation of expression of different Reg genes. In addition, the pathways relaying Reg-triggered signals, their targets and potential cross-talk with other cascades are still largely unknown. In this review, the expression patterns of different Reg members in the pancreas and extrapancreatic tissues are described. Moreover, factors known to modulate Reg levels in different cell types are discussed. Several signaling pathways, which have been implicated in conferring the effects of Reg ligands to date, are also delineated. Further efforts are necessary for elucidating the biological processes underlying the action of Reg proteins and their involvement in various maladies. Better understanding of the function of Reg genes and proteins will be beneficial in the design and development of therapies utilizing or targeting this protein group.
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Affiliation(s)
- Abhirath Parikh
- Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, NY 14260
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31
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Planas R, Pujol-Autonell I, Ruiz E, Montraveta M, Cabre E, Lucas-Martin A, Pujol-Borrell R, Martinez-Caceres E, Vives-Pi M. Regenerating gene Iα is a biomarker for diagnosis and monitoring of celiac disease: a preliminary study. Transl Res 2011; 158:140-5. [PMID: 21867979 DOI: 10.1016/j.trsl.2011.04.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Revised: 04/20/2011] [Accepted: 04/25/2011] [Indexed: 12/14/2022]
Abstract
The regenerating gene (REG) is a multigene family in humans that plays a role in tissue regeneration. The REG Iα protein is expressed in the pancreas and the gastrointestinal tract and is involved in the pathophysiology of gastritis, pancreatitis, cancer, inflammatory bowel disease, and type 1 diabetes (T1D). Celiac disease (CD) is an autoimmune disease caused by the ingestion of gluten in genetically susceptible individuals. Our aim was to determine whether the serum REG Iα concentration reflects the destructive/regenerative process in the small bowel in CD. REG Iα was determined by enzyme-linked immunosorbent assay (ELISA) in 40 patients with active CD, and in 19 of them, REG Iα was assessed after following a gluten free diet. As controls, 35 healthy subjects were included in the study. Autoantibodies to transglutaminase, gliadin, and endomisium were measured also. We found a significant increase in REG Iα in the sera of CD patients when compared with controls. REG Iα levels decreased after a gluten-free diet together with a significant reduction in antitransglutaminase antibodies. T1D and pernicious anemia patients displayed normal serum REG Iα concentrations. This preliminary study suggests that REG Iα protein levels can be used as a biomarker for the diagnosis and monitoring of CD.
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Affiliation(s)
- Raquel Planas
- Laboratory of Immunobiology for Research and Diagnosis Applications (LIRAD), Blood and Tissue Bank, Germans Trias i Pujol Research Institute, Carretera Canyet s/n, Badalona, Spain
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32
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Gao P, Jiao Y, Xiong Q, Wang CY, Gerling I, Gu W. Genetic and Molecular Basis of QTL of Diabetes in Mouse: Genes and Polymorphisms. Curr Genomics 2011; 9:324-37. [PMID: 19471607 PMCID: PMC2685644 DOI: 10.2174/138920208785133253] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2008] [Revised: 04/14/2008] [Accepted: 04/17/2008] [Indexed: 12/14/2022] Open
Abstract
A systematic study has been conducted of all available reports in PubMed and OMIM (Online Mendelian Inheritance in Man) to examine the genetic and molecular basis of quantitative genetic loci (QTL) of diabetes with the main focus on genes and polymorphisms. The major question is, What can the QTL tell us? Specifically, we want to know whether those genome regions differ from other regions in terms of genes relevant to diabetes. Which genes are within those QTL regions, and, among them, which genes have already been linked to diabetes? whether more polymorphisms have been associated with diabetes in the QTL regions than in the non-QTL regions. Our search revealed a total of 9038 genes from 26 type 1 diabetes QTL, which cover 667,096,006 bp of the mouse genomic sequence. On one hand, a large number of candidate genes are in each of these QTL; on the other hand, we found that some obvious candidate genes of QTL have not yet been investigated. Thus, the comprehensive search of candidate genes for known QTL may provide unexpected benefit for identifying QTL genes for diabetes.
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Affiliation(s)
- Peng Gao
- Departments of Orthopaedic Surgery, Campbell Clinic and Pathology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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33
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Chen JJ, Wang R, Li XF, Wang RL. Bifidobacterium longum supplementation improved high-fat-fed-induced metabolic syndrome and promoted intestinal Reg I gene expression. Exp Biol Med (Maywood) 2011; 236:823-31. [PMID: 21685239 DOI: 10.1258/ebm.2011.010399] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Recent evidence suggests that intestinal Bifidobacterium species (spp.) positively correlates with improved insulin resistance and obesity, and this might be linked to metabolic inflammation. The expression of intestinal REG (regenerating) family proteins which are widely involved in inflammatory bowel disease and diabetes are still unknown in metabolic syndrome. Hence, we investigated the effects of Bifidobacterium longum (BIF) supplementation on metabolic parameters, intestinal function and expression of Reg family genes in a rat model of metabolic syndrome induced by a high-fat (HF) diet. We specifically increased the gut bifidobacterial content of HF-fed rats through BIF supplementation. Compared with the normal chow-fed control rats, HF feeding significantly reduced intestinal Bifidobacterium. As expected, BIF supplementation fed rats had totally restored quantities of Bifidobacterium. HF diet-fed rats showed significant increase in body weight, fat deposits, systolic blood pressure, fasting glucose, fasting triglycerides and reduced insulin sensitivity, while increases of intestinal Bifidobacterium did improve HF-diet-induced metabolic disorders. HF feeding led to significantly higher levels of the plasma lipopolysaccharide, interleukin-1β and intestinal myeloperoxidase, as well as intestinal inflammatory activity index, while these parameters were normalized to the control levels in the HF + BIF-treated rats. The levels of RegI mRNA and protein in the HF + BIF group were significantly higher than the control and the HF groups. Increasing Bifidobacterium in the gut improved HF-fed-induced metabolic syndrome by reducing metabolic endotoxin concentrations and intestinal inflammation, as well as upgrading the expression of intestinal Reg I as a regulator of growth factor.
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Affiliation(s)
- Jin Jin Chen
- Children Health Care Center, Shanghai Children's Hospital-Shanghai Jiaotong University, No. 24 Ln. 1400 West Beijing Road, Shanghai, China.
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34
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Xiong X, Wang X, Li B, Chowdhury S, Lu Y, Srikant CB, Ning G, Liu JL. Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus. Am J Physiol Endocrinol Metab 2011; 300:E669-80. [PMID: 21245462 DOI: 10.1152/ajpendo.00600.2010] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Reg family proteins have been implicated in islet β-cell proliferation, survival, and regeneration. The expression of Reg3β (pancreatitis-associated protein) is highly induced in experimental diabetes and acute pancreatitis, but its precise role has not been established. Through knockout studies, this protein was shown to be mitogenic, antiapoptotic, and anti-inflammatory in the liver and pancreatic acinars. To test whether it can promote islet cell growth or survival against experimental damage, we developed β-cell-specific overexpression using rat insulin I promoter, evaluated the changes in normal islet function, gene expression profile, and the response to streptozotocin-induced diabetes. Significant and specific overexpression of Reg3β was achieved in the pancreatic islets of RIP-I/Reg3β mice, which exhibited normal islet histology, β-cell mass, and in vivo and in vitro insulin secretion in response to high glucose yet were slightly hyperglycemic and low in islet GLUT2 level. Upon streptozotocin treatment, in contrast to wild-type littermates that became hyperglycemic in 3 days and lost 15% of their weight, RIP-I/Reg3β mice were significantly protected from hyperglycemia and weight loss. To identify specific targets affected by Reg3β overexpression, a whole genome DNA microarray on islet RNA isolated from the transgenic mice revealed more than 45 genes significantly either up- or downregulated. Among them, islet-protective osteopontin/SPP1 and acute responsive nuclear protein p8/NUPR1 were significantly induced, a result further confirmed by real-time PCR, Western blots, and immunohistochemistry. Our results suggest that Reg3β is unlikely an islet growth factor but a putative protector that prevents streptozotocin-induced damage by inducing the expression of specific genes.
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Affiliation(s)
- Xiaoquan Xiong
- Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
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35
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Neurath MF, Finotto S. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev 2011; 22:83-9. [PMID: 21377916 DOI: 10.1016/j.cytogfr.2011.02.003] [Citation(s) in RCA: 438] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
IL-6 activates various cell types carrying the membrane bound IL-6R (classical IL-6 signaling) as well as IL-6R(-) gp130(+) cells via the soluble IL-6R (IL-6 trans-signaling). IL-6 signaling plays a pivotal role in controlling the differentiation and activation of T lymphocytes by inducing the Jak/STAT-3 and the Ras/Erk/C/EBP pathways. In particular, IL-6 modulates the resistance of T cells against apoptosis, induces activation of T helper cells and controls the balance between regulatory T cells and Th17 cells. Importantly, recent findings suggest that blockade of IL-6 signaling is effective in treating experimental models of autoimmune and chronic inflammatory diseases such as inflammatory bowel diseases, diabetes, multiple sclerosis, asthma and rheumatoid arthritis as well as models of inflammation-associated cancer. Thus, anti-IL-6/anti-IL-6R strategies emerge as promising novel approaches for therapy of inflammatory diseases in humans. In this review article, we discuss the latest findings on the role of IL-6 in experimental models of autoimmunity and cancer, as well as clinical perspectives.
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Abstract
The widely used nonobese diabetic (NOD) mouse model of autoimmune (Type 1) diabetes mellitus shares multiple characteristics with the human disease, and studies employing this model continue to yield clinically relevant and important information. Here, we review some of the recent key findings obtained from NOD mouse investigations that have both advanced our understanding of disease pathogenesis and suggested new therapeutic targets and approaches. Areas discussed include antigen discovery, identification of genes and pathways contributing to disease susceptibility, development of strategies to image islet inflammation and the testing of therapeutics. We also review recent technical advances that, combined with an improved understanding of the NOD mouse model's limitations, should work to ensure its popularity, utility and relevance in the years ahead.
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Affiliation(s)
- Rodolfo José Chaparro
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Teresa P DiLorenzo
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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37
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Babad J, Geliebter A, DiLorenzo TP. T-cell autoantigens in the non-obese diabetic mouse model of autoimmune diabetes. Immunology 2010; 131:459-65. [PMID: 21039471 DOI: 10.1111/j.1365-2567.2010.03362.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The non-obese diabetic (NOD) mouse model of autoimmune (type 1) diabetes has contributed greatly to our understanding of disease pathogenesis and has facilitated the development and testing of therapeutic strategies to combat the disease. Although the model is a valuable immunological tool in its own right, it reaches its fullest potential in areas where its findings translate to the human disease. Perhaps the foremost example of this is the field of T-cell antigen discovery, from which diverse benefits can be derived, including the development of antigen-specific disease interventions. The majority of NOD T-cell antigens are also targets of T-cell autoimmunity in patients with type 1 diabetes, and several of these are currently being evaluated in clinical trials. Here we review the journeys of these antigens from bench to bedside. We also discuss several recently identified NOD T-cell autoantigens whose translational potential warrants further investigation.
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Affiliation(s)
- Jeffrey Babad
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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38
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Hamden K, Masmoudi H, Carreau S, Elfeki A. Immunomodulatory, beta-cell, and neuroprotective actions of fenugreek oil from alloxan-induced diabetes. Immunopharmacol Immunotoxicol 2010; 32:437-445. [PMID: 20100065 DOI: 10.3109/08923970903490486] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Immunological disorders and nephropathy are among the most frequent and serious complications of diabetes mellitus. This shows that fewer infiltrated inflammatory cells evidenced by reverted back to near the normal value of white blood cell, mean corpuscular volume, and lymphocytes counts as interleukin-6 in pancreas. Also, fenugreek oil significantly improved blood glucose levels, glucose intolerance, and insulin sensitivity compared to the diabetic group. The pancreatic islet and less beta-cells damage were observed after the administration of fenugreek oil to diabetic rats. Moreover, diabetic rats showed low activities of superoxide dismutase, catalase, glutathione peroxidase, and reduced glutathione content in kidney, which were restored to near normal levels by treatment with fenugreek oil. The increased levels of lipid peroxidation, creatinine, albumin, and urea in diabetic rats decreased significantly in diabetic rats treated with fenugreek oil. Diabetic rats treated with fenugreek oil restored almost a normal architecture of pancreas and kidney. In conclusion, this study reveals the efficacy of fenugreek oil in the amelioration of diabetes, hematological status, and renal toxicity which may be attributed to its immunomodulatory activity and insulin stimulation action along with its antioxidant potential.
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Affiliation(s)
- Khaled Hamden
- Animal Ecophysiology Laboratory, Faculty of Sciences of Sfax, University of Sfax, Sfax, Tunisia.
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39
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Li FY, Ren XB, Xu EP, Huang Q, Sheng HQ, Lv BJ, Lai MD. RegIV expression showing specificity to gastrointestinal tract and its potential role in diagnosing digestive tract neuroendocrine tumor. J Zhejiang Univ Sci B 2010; 11:258-66. [PMID: 20349522 DOI: 10.1631/jzus.b0900383] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Regenerating gene IV (RegIV), a member of the regenerating gene family discovered in 2001, has been found to be involved in malignancy in several different organs including the stomach, colorectum, pancreas and prostate, but the overall expression profile of RegIV has not been reported. To learn more about RegIV, we evaluated its distribution by immunohistochemistry (IHC) in a total of 360 samples including 24 types of normal tissue, 40 benign and malignant lesions, and 18 neuroendocrine tumors. We found that in normal tissues, in addition to its relative specificity for the gastrointestinal tract, RegIV was detected in the adrenal gland and mammary gland. Among all the malignancies of various histological types under evaluation, RegIV was found mostly in adenocarcinomas. Studies on additional sets of colorectal tumor samples showed that RegIV expression was predominant in colorectal adenoma (87.5%) and peritumoral tissue (100%) but not in cancer tissue (30.8%). Among neuroendocrine tumors, RegIV had a relatively restricted expression to those of digestive system.
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Affiliation(s)
- Feng-ying Li
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, China
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40
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Levetan C. Distinctions between islet neogenesis and β-cell replication: implications for reversal of Type 1 and 2 diabetes. J Diabetes 2010; 2:76-84. [PMID: 20923488 DOI: 10.1111/j.1753-0407.2010.00074.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The terms "islet" and "β-cell" are often used interchangeably, yet islets are highly complex multicellular organelles that contain the insulin-producing β-cells and four other cells types, all of which play a role in maintaining glucose homeostasis within a very narrow range. Although the formation of new islets in adults is rare, occurring primarily in response to pancreatic injury and major stress to the pancreas, β-cell replication from existing cells occurs throughout adulthood. An understanding of the regulatory factors controlling pancreatic development has more clearly defined the differences between new islet formation from progenitor cells located throughout the adult pancreas and β-cell replication occurring within existing islets. The present review sets forth to more clearly distinguish the differences between the postnatal pathways of islet neogenesis and β-cell replication with a discussion of the potential implications for reversal of Type 1 and 2 diabetic patients using islet neogenesis agents that are now in development. For Type 1 diabetic patients, an immune tolerance agent in conjunction with an islet neogenesis agent may allow achievement of adequate islet mass, perhaps with subsequent potential to withdraw medications. For Type 2 diabetic patients, lifestyle changes and/or medications may sustain the production of new islets and limit the accelerated β-cell apoptosis characteristic of the condition.
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Affiliation(s)
- Claresa Levetan
- Division of Endocrinology, Chestnut Hill Hospital, Philadelphia, Pennsylvania, USA.
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41
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Planas R, Carrillo J, Sanchez A, de Villa MCR, Nuñez F, Verdaguer J, James RFL, Pujol-Borrell R, Vives-Pi M. Gene expression profiles for the human pancreas and purified islets in type 1 diabetes: new findings at clinical onset and in long-standing diabetes. Clin Exp Immunol 2010; 159:23-44. [PMID: 19912253 PMCID: PMC2802692 DOI: 10.1111/j.1365-2249.2009.04053.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/13/2009] [Indexed: 11/30/2022] Open
Abstract
Type 1 diabetes (T1D) is caused by the selective destruction of the insulin-producing beta cells of the pancreas by an autoimmune response. Due to ethical and practical difficulties, the features of the destructive process are known from a small number of observations, and transcriptomic data are remarkably missing. Here we report whole genome transcript analysis validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and correlated with immunohistological observations for four T1D pancreases (collected 5 days, 9 months, 8 and 10 years after diagnosis) and for purified islets from two of them. Collectively, the expression profile of immune response and inflammatory genes confirmed the current views on the immunopathogenesis of diabetes and showed similarities with other autoimmune diseases; for example, an interferon signature was detected. The data also supported the concept that the autoimmune process is maintained and balanced partially by regeneration and regulatory pathway activation, e.g. non-classical class I human leucocyte antigen and leucocyte immunoglobulin-like receptor, subfamily B1 (LILRB1). Changes in gene expression in islets were confined mainly to endocrine and neural genes, some of which are T1D autoantigens. By contrast, these islets showed only a few overexpressed immune system genes, among which bioinformatic analysis pointed to chemokine (C-C motif) receptor 5 (CCR5) and chemokine (CXC motif) receptor 4) (CXCR4) chemokine pathway activation. Remarkably, the expression of genes of innate immunity, complement, chemokines, immunoglobulin and regeneration genes was maintained or even increased in the long-standing cases. Transcriptomic data favour the view that T1D is caused by a chronic inflammatory process with a strong participation of innate immunity that progresses in spite of the regulatory and regenerative mechanisms.
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MESH Headings
- Adolescent
- Adult
- Antigens, CD/analysis
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- C-Reactive Protein/genetics
- C-Reactive Protein/metabolism
- Cell Count
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/pathology
- Down-Regulation/genetics
- Female
- Gene Expression/genetics
- Gene Expression Profiling
- Glucagon-Secreting Cells/metabolism
- HLA Antigens/genetics
- HLA Antigens/metabolism
- Histocompatibility Antigens Class I/genetics
- Histocompatibility Antigens Class I/metabolism
- Humans
- Immunity, Innate/genetics
- Inflammation/genetics
- Insulin-Secreting Cells/metabolism
- Islets of Langerhans/metabolism
- Islets of Langerhans/pathology
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Leukocytes/metabolism
- Male
- Middle Aged
- Pancreas/metabolism
- Pancreas/pathology
- Pancreatitis-Associated Proteins
- Reverse Transcriptase Polymerase Chain Reaction
- Up-Regulation/genetics
- Young Adult
- HLA-E Antigens
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Affiliation(s)
- R Planas
- Laboratory of Immunobiology for Research and Applications to Diagnosis (LIRAD), Research Institute Germans Trias i Pujol, Badalona, Spain
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Cui W, De Jesus K, Zhao H, Takasawa S, Shi B, Srikant CB, Liu JL. Overexpression of Reg3alpha increases cell growth and the levels of cyclin D1 and CDK4 in insulinoma cells. Growth Factors 2009; 27:195-202. [PMID: 19343564 DOI: 10.1080/08977190902863548] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Regenerating gene (Reg) family protein Reg3alpha is normally expressed in pancreatic acinar and endocrine cells. In order to explore its effect on islet beta-cell replication, insulinoma MIN6 cells were stably transfected with murine Reg3alpha cDNA. Determined using real-time PCR and Western blots, the levels of Reg3alpha mRNA and protein in Reg3alpha-transfected clones were increased 10- and 6-fold, respectively. Western blots also revealed that the protein was released into the culture medium, consistent with an endocrine effect. In MTT cell proliferation assay, Reg3alpha-overexpressing cells exhibited a 2-fold increase in the rate of cell growth. In order to investigate the intracellular mechanism, we studied cell cycle regulatory proteins. In Reg3alpha-expressing cells, we detected 2.2- and 2.5-fold increased levels of cyclin D1 and CDK4, respectively, which paralleled a 1.8-fold increase in the rate of Akt phosphorylation. It is established that beta-cell replication is associated with increased cyclin D1 and CDK4 levels; deficiency in CDK4 or cyclin D2 results in reduced beta-cell mass and diabetes. Our results suggest that Reg3alpha stimulates beta-cell replication, by activating Akt kinase and increasing the levels of cyclin D1/CDK4.
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Affiliation(s)
- Wei Cui
- School of Medicine, The First Affiliated Hospital, Xi'an Jiao Tong University, Xi'an, Shaanxi, PR China
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43
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Abstract
OBJECTIVE Beta-cell regeneration is a fundamental but elusive goal for type 1 diabetes research. Our objective is to review newer human and animal studies of beta-cell destruction and regeneration and consider the implications for treatment of type 1 diabetes. RESEARCH DESIGN AND METHODS Recent human and animal studies of beta-cell destruction and regeneration in type 1 diabetes are reviewed. RESULTS The loss of beta-cells that characterizes type 1 diabetes reflects the net effects of destruction and regeneration. These processes have been examined in the nonobese diabetic (NOD) mouse; uncertainty remains about beta-cell dynamics in humans. Islet inflammation stimulates beta-cell replication that produces new insulin-positive cells. The regenerative process may tide the loss of overall beta-cell function, but it also may enhance the autoimmune attack on beta-cells by providing new epitopes. The highest rates of beta-cell replication are at the time of diagnosis of diabetes in NOD mice, and if autoimmunity and islet inflammation are arrested, new beta-cells are formed. However, the majority of beta-cells after treatment with immune modulators such as anti-CD3 monoclonal antibody, and most likely during the "honeymoon" in human disease, are recovered beta-cells that had been degranulated but present at the time of diagnosis of diabetes. CONCLUSIONS Residual beta-cells play a significant role for the design of therapeutic trials: they not only may respond to combination therapies that include stimulants of metabolic function but are also the potential source of new beta-cells.
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Affiliation(s)
- Eitan Akirav
- Department of Immunobiology, Yale University, New Haven, Connecticut, USA
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44
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Ihm SH, Matsumoto I, Zhang HJ, Ansite JD, Hering BJ. Effect of short-term culture on functional and stress-related parameters in isolated human islets. Transpl Int 2008; 22:207-16. [DOI: 10.1111/j.1432-2277.2008.00769.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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45
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IL-21 signaling is critical for the development of type I diabetes in the NOD mouse. Proc Natl Acad Sci U S A 2008; 105:14028-33. [PMID: 18779574 DOI: 10.1073/pnas.0804358105] [Citation(s) in RCA: 169] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
IL-21 is a pleiotropic type I cytokine that shares the common cytokine receptor gamma chain and plays important roles for normal Ig production, terminal B cell differentiation to plasma cells, and Th17 differentiation. IL-21 is elevated in several autoimmune diseases, and blocking its action has attenuated disease in MRL/lpr mice and in collagen-induced arthritis. The diabetes-associated Idd3 locus is at the Il2/Il21 locus, and elevated IL-21 was observed in the nonobese diabetic (NOD) mouse and suggested to contribute to diabetes by augmenting T cell homeostatic proliferation. To determine the role of IL-21 in diabetes, Il21r-knockout (KO) mice were backcrossed to NOD mice. These mice were devoid of lymphocytic infiltration into the pancreas, and only 1 of 20 animals had an elevated glucose compared with 60% of NOD mice on a wild-type (WT) background. Although TCR and Treg-related responses were normal, these mice had reduced Th17 cells and significantly higher levels of mRNAs encoding members of the Reg (regenerating) gene family whose transgenic expression protects against diabetes. Our studies establish a critical role for IL-21 in the development of type I diabetes in the NOD mouse, with obvious potential implications for type I diabetes in humans.
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46
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Castellarin ML, Petropavlovskaia M, Lipsett MA, Rosenberg L. The identification and sequence analysis of a new Reg3gamma and Reg2 in the Syrian golden hamster. ACTA ACUST UNITED AC 2007; 1769:579-85. [PMID: 17673309 DOI: 10.1016/j.bbaexp.2007.06.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2007] [Revised: 06/04/2007] [Accepted: 06/15/2007] [Indexed: 11/16/2022]
Abstract
The regenerating (Reg) genes are associated with tissue repair and have been directly implicated in pancreatic beta-cell regeneration. A hamster Reg3, Islet neogenesis associated protein (INGAP), has been shown to possess anti-diabetic properties in rodent models. Although several Reg3 proteins have been identified in other species, INGAP is the only Reg3 found in hamsters. To identify new Reg3 genes in the hamster pancreas we employed homology reverse transcription polymerase chain reaction (RT-PCR) using degenerate Reg3 primers, followed by rapid amplification of cDNA ends (RACE). We report here the discovery of a new hamster Reg3 gene of 765 nucleotides (nt) that encodes a 174-amino acid (aa) protein. This protein sequence was identified as a novel hamster Reg3gamma with 78% and 75% identity to the rat Reg3gamma and mouse Reg3gamma protein, respectively. We also fully sequenced the previously reported partial sequence of the hamster Reg1 gene coding region using RACE to yield a 756-nt transcript that encodes a deduced 173 aa protein. This protein was identified as hamster Reg2, rather than Reg1 as was initially reported, with an 81% identity to mouse Reg2. The spatial gene expression patterns of the hamster Reg genes, analyzed by RT-PCR, were similarly distributed with low level expression being found globally throughout the body. Mice and hamsters are the only species known to carry either of the functional INGAP or Reg2 genes. It remains to be determined whether these genes bestow mice and hamsters with special regenerative abilities in the pancreas.
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Affiliation(s)
- Mauro L Castellarin
- Research Institute of The McGill University Health Centre and The Department of Surgery, McGill University, C9-128 The Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec, Canada H3G 1A4
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47
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Leptin induces inflammation-related genes in RINm5F insulinoma cells. BMC Mol Biol 2007; 8:41. [PMID: 17521427 PMCID: PMC1890559 DOI: 10.1186/1471-2199-8-41] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2006] [Accepted: 05/23/2007] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Leptin acts not only on hypothalamic centers to control food intake but has additional functions in peripheral tissues, e.g. inhibition of insulin secretion from pancreatic islets. The leptin receptor (LEPRb) is a class I cytokine receptor that mediates activation of STAT transcription factors. In this study, we characterise the regulation of inflammation-related genes by leptin in insulinoma cells and compare the effect of transcriptional regulation by leptin with that of other cytokines. RESULTS We have used RINm5F insulinoma cells as a model system for a peripheral target cell of leptin. Six transcripts encoding inflammation-related proteins were found to be upregulated by activation of LEPRb, namely lipocalin-2, pancreatitis-associated protein, preprotachykinin-1, fibrinogen-beta, tissue-type plasminogen activator (tPA) and manganese-dependent superoxide dismutase (MnSOD). Four of these transcripts (fibrinogen-beta, lipocalin-2, tPA, MnSOD) were also induced by the proinflammatory cytokine interleukin-1beta (IL-1beta). Interferon-gamma alone had no effect on the leptin-induced transcripts but enhanced the upregulation by IL-1beta of lipocalin-2, tPA and MnSOD mRNA levels. Experiments with LEPRb point mutants revealed that the upregulation of the inflammation-related genes depended on the presence of tyrosine-1138 which mediates the activation of the transcription factors STAT1 and STAT3. Reporter gene assays showed that leptin induced the expression of preprotachykinin-1 and lipocalin-2 on the level of promoter regulation. Finally, leptin treatment increased caspase 3-like proteolytic activity in RINm5F cells. CONCLUSION The present data show that leptin induces a cytokine-like transcriptional response in RINm5F cells, consistent with the proposed function of leptin as a modulator of immune and inflammatory responses.
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48
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Abstract
The Reg family of proteins has been studied in the context of growth and regeneration in several organs including pancreatic islets. We previously suggested that Reg proteins act as autoantigens in type 1 diabetes, based on evidence that a member of the Reg family (hepatocellular carcinoma intestine pancreas [HIP]/pancreatitis-associated protein [PAP]) was overexpressed in the islets of a patient who died after sudden onset of type 1 diabetes, and that, in NOD mice, Reg-specific T-cells adoptively transferred diabetes. In the current study, we developed antisera to detect individual Reg members in mouse islets and found that RegIIIalpha was present in the non-beta-cell portion of the islets, while RegII was predominantly expressed in beta-cells. Vaccination of NOD mice with the separately expressed N-terminal (NtfrII) or C-terminal (CtfrII) portion of RegII revealed a dichotomy: NtfrII vaccination accelerated and CtfrII vaccination delayed type 1 diabetes. Vaccination with CtfrII was more effective when given at later stages in the pathogenesis of type 1 diabetes, a time dependency different from that seen with other antigen-dependent vaccine strategies in NOD mice, which might have therapeutic implications. In conclusion, RegII is a novel beta-cell-derived autoantigen in NOD mice. The autoimmune response against this protein may convert a regenerative into an islet-destructive process accelerating development of type 1 diabetes.
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Affiliation(s)
- Werner Gurr
- Yale University School of Medicine, Section of Endocrinology, New Haven, CT 06520-8020, USA.
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49
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Planas R, Alba A, Carrillo J, Puertas MC, Ampudia R, Pastor X, Okamoto H, Takasawa S, Gurr W, Pujol-Borrell R, Verdaguer J, Vives-Pi M. Reg (regenerating) gene overexpression in islets from non-obese diabetic mice with accelerated diabetes: role of IFNbeta. Diabetologia 2006; 49:2379-87. [PMID: 16900387 DOI: 10.1007/s00125-006-0365-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2006] [Accepted: 06/01/2006] [Indexed: 12/17/2022]
Abstract
AIMS/HYPOTHESIS The expression of IFNbeta in beta cells results in accelerated type 1 diabetes. The REG family of beta cell proliferation factors have been described as autoantigens in autoimmune diabetes. The aim of this study was to determine the effect of IFNbeta on Reg expression, and the implications of this in terms of autoimmunity. METHODS Reg gene expression was determined in islets from non-obese diabetic (NOD) RIP-HuIFNbeta mice by cDNA microarray, quantitative real-time PCR and immunohistochemistry. The effect of IFNbeta on Reg1 and Reg2 expression was assessed in the NOD insulinoma cell line NIT-1. IL-6, known to induce Reg expression, was measured in the insulitis microenvironment. Morphological studies were carried out to determine islet enlargement in this model. RESULTS Reg2 was upregulated in islets from the NOD RIP-HuIFNbeta mice at the onset of the autoimmune attack. IFNbeta upregulates Reg1 and Reg2 genes in NIT-1 cells. The expression of Il6 was increased in islets from transgenic mice and in NIT-1 cells exposed to HuIFNbeta. Moreover, islets from transgenic mice were enlarged compared with those from wild-type mice. CONCLUSIONS/INTERPRETATION Reg overexpression correlates well with the acceleration of diabetes in this model. The upregulation of Reg suggests that islets try to improve hyperglycaemia by regenerating the cells lost in the autoimmune attack. Reg expression is regulated by several factors such as inflammation. Therefore, the overexpression of an IFNbeta-induced autoantigen (REG) in the islets during inflammation might contribute to the premature onset of diabetes.
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Affiliation(s)
- R Planas
- Laboratory of Immunobiology for Research and Diagnostic Applications (LIRAD), Blood and Tissue Bank, Germans Trias i Pujol University Hospital, PO Box 72, 08916, Badalona, Barcelona, Spain
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50
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Lu Y, Ponton A, Okamoto H, Takasawa S, Herrera PL, Liu JL. Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas. Am J Physiol Endocrinol Metab 2006; 291:E50-8. [PMID: 16449294 PMCID: PMC2950860 DOI: 10.1152/ajpendo.00596.2005] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We have recently reported that Pdx1-Cre-mediated whole pancreas inactivation of IGF-I gene [in pancreatic-specific IGF-I gene-deficient (PID) mice] results in increased beta-cell mass and significant protection against both type 1 and type 2 diabetes. Because the phenotype is unlikely a direct consequence of IGF-I deficiency, the present study was designed to explore possible activation of proislet factors in PID mice by using a whole genome DNA microarray. As a result, multiple members of the Reg family genes (Reg2, -3alpha, and -3beta, previously not known to promote islet cell growth) were significantly upregulated in the pancreas. This finding was subsequently confirmed by Northern blot and/or real-time PCR, which exhibited 2- to 8-fold increases in the levels of these mRNAs. Interestingly, these Reg family genes were also activated after streptozotocin-induced beta-cell damage and diabetes (wild-type T1D mice) when islet cells were undergoing regeneration. Immunohistochemistry revealed increased Reg proteins in exocrine as well as endocrine pancreas and suggested their potential role in beta-cell neogenesis in PID or T1D mice. Previously, other Reg proteins (Reg1 and islet neogenesis-associated protein) have been shown to promote islet cell replication and neogenesis. These uncharacterized Reg proteins may play a similar but more potent role, not only in normal islet cell growth in PID mice, but also in islet cell regeneration after T1D.
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MESH Headings
- Animals
- Blotting, Northern
- Crosses, Genetic
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/pathology
- Female
- Gene Expression Regulation
- Immunohistochemistry
- Insulin-Like Growth Factor I/deficiency
- Insulin-Like Growth Factor I/genetics
- Islets of Langerhans/metabolism
- Islets of Langerhans/pathology
- Lithostathine/biosynthesis
- Lithostathine/genetics
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mice, Transgenic
- Oligonucleotide Array Sequence Analysis
- Pancreatitis-Associated Proteins
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Reverse Transcriptase Polymerase Chain Reaction
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Affiliation(s)
- Yarong Lu
- Fraser Laboratories, Rm. M3-15, Royal Victoria Hospital, 687 Pine Ave. West, Montreal, QC H3A 1A1, Canada
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