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Stepanov YM, Tarasova TS, Stoikevych MV, Gaydar YA, Mylostуva DF, Tatarchuk ОM, Petishko OP. Diagnosis of inflammatory bowel disease according to human IgG4 and possibilities of evaluating efficacy of the therapy. REGULATORY MECHANISMS IN BIOSYSTEMS 2022. [DOI: 10.15421/022254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023] Open
Abstract
Taking into account the progress of understanding diagnosis, course prognosis, evaluation of effectiveness of therapy of inflammatory bowel disease and also differentiation diagnosis between its main forms – ulcerative colitis and Crohn’s disease, the search for efficient non-invasive markers for solving those issues is extremely relevant. The patients were divided into groups depending on nosology and severity of the course of the disease. All the patients had undergone endoscopic study for diagnosis verification and biopsy samples were taken for further detection of tissue IgG4 using the immunohistochemical method. Also, we determined concentration of serum IgG4. Increase in IgG4content in blood serum was determined in 54.0% of the cases of inflammatory bowel disease. Concentration of IgG4 in patients suffering ulcerative colitis was higher (by 2.31 and 2.46 times) compared with its level in the control group and patients with Crohn’s disease, respectively. We found relationships between the concentration of serum IgG4 and the activity of the disease. In patients with ulcerative colitis, increased tissue IgG4 was found more often than in patients with Crohn’s disease (by 2.77 times, Р < 0.05). We determined the relationship between tissue IgG4 and histological activity. Simultaneous increase in serum IgG4 and presence of tissue IgG4 during ulcerative colitis were more frequent than during Crohn’s disease (by 2.66 times). In all examined groups of patients, we determined decrease in serum IgG4 content (by 1.66 times) after treatment. Concentration of serum IgG4 and positive tissue IgG4 in ulcerative colitis patients exceeded such in Crohn’s disease patients, which may be used for differentiation diagnosis between those disease types. We determined dependence of IgG4 concentration on severity and duration of the disease, which could be used as a prognostic marker. Decrease in IgG4 content in blood serum against the background of the therapy shows that this indicator could be used as a marker of treatment efficacy. Perspectives of further studies are as follows: parameters of concentration of serum IgG4 and presence of tissue IgG4 could be used as diagnostic and prognostic biomarkers and be introduced to practice for differentiation diagnosis between ulcerative colitis and Crohn’s disease, and could be used as prognostic marker of severity of the disease and therapy efficacy.
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Yoon B, Yun Y, Kim KB, Kim DE. Inhibition of immunoproteasome attenuates NLRP3 inflammasome formation in tumor necrosis factor α-stimulated intestinal epithelial cell. Biochem Biophys Res Commun 2022; 624:157-163. [PMID: 35944388 PMCID: PMC10913474 DOI: 10.1016/j.bbrc.2022.07.120] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 07/29/2022] [Accepted: 07/31/2022] [Indexed: 11/26/2022]
Abstract
Excessive release of inflammatory cytokines has been considered as a major cause of chronic inflammation, resulting in intestinal barrier disruption that leads to inflammatory bowel disease (IBD). Tumor necrosis factor α (TNFα) is one of the well-known inflammatory cytokines that activates formation of NLRP3 inflammasome, thus resulting in excessive secretion of inflammatory cytokines causing IBD. Although immunoproteasome inhibitors have been reported to inhibit inflammatory cytokine release, immunoproteasome inhibition has not yet been addressed for attenuation of NLRP3 inflammasome activity in intestinal epithelial cell. Here, we observed that NLRP3 inflammasome assembly was attenuated by peptide epoxyketone YU102, a LMP2 subunit immunoproteasome inhibitor, in intestinal epithelial cell. YU102 also inhibited maturation of active caspase-1 and secretion of IL-1β, which are subsequent inflammatory cascade after the formation of NLRP3 inflammasome. Progression of epithelial-mesenchymal transition and increase of cellular permeability, which were induced by TNFα, were also suppressed through inhibition of immunoproteasome. Furthermore, we found that YU102 does not inhibit degradation of IкBα and its following NF-кB activation that leads to transcription of NLRP3. These findings suggest that inhibition of immunoproteasome with YU102 offers a potential therapeutic premise for prevention of TNFα-induced chronic inflammation through attenuation of NLRP3 inflammasome assembly.
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Affiliation(s)
- Boran Yoon
- Department of Bioscience and Biotechnology, Konkuk University, Neundong-ro 120, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Yewon Yun
- Department of Bioscience and Biotechnology, Konkuk University, Neundong-ro 120, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Kyung Bo Kim
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536-0596, United States
| | - Dong-Eun Kim
- Department of Bioscience and Biotechnology, Konkuk University, Neundong-ro 120, Gwangjin-gu, Seoul, 05029, Republic of Korea.
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Camba-Gómez M, Arosa L, Gualillo O, Conde-Aranda J. Chemokines and chemokine receptors in inflammatory bowel disease: Recent findings and future perspectives. Drug Discov Today 2021; 27:1167-1175. [PMID: 34896626 DOI: 10.1016/j.drudis.2021.12.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 11/11/2021] [Accepted: 12/06/2021] [Indexed: 11/03/2022]
Abstract
Despite the benefits of current therapeutic options for treating inflammatory bowel disease (IBD), there are still patients who are refractory to these therapies. Moreover, the relapses caused by incomplete intestinal mucosa healing are frequent. Therefore, there is a need for novel pharmacological targets that can improve the existing IBD therapeutic armamentarium. Chemokine and chemokine receptors have emerged as appealing options to this end. As well as controlling leukocyte trafficking to inflamed tissues, these proteins regulate many other processes related to the development of intestinal inflammation. In this review, we summarise the most recent preclinical studies, along with the putative application of chemokine-based therapies in patients with IBD.
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Affiliation(s)
- Miguel Camba-Gómez
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Laura Arosa
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Javier Conde-Aranda
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
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Ocansey DKW, Pei B, Xu X, Zhang L, Olovo CV, Mao F. Cellular and molecular mediators of lymphangiogenesis in inflammatory bowel disease. J Transl Med 2021; 19:254. [PMID: 34112196 PMCID: PMC8190852 DOI: 10.1186/s12967-021-02922-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/02/2021] [Indexed: 02/07/2023] Open
Abstract
Background Recent studies reporting the intricate crosstalk between cellular and molecular mediators and the lymphatic endothelium in the development of inflammatory bowel diseases (IBD) suggest altered inflammatory cell drainage and lymphatic vasculature, implicating the lymphatic system as a player in the occurrence, development, and recurrence of intestinal diseases. This article aims to review recent data on the modulatory functions of cellular and molecular components of the IBD microenvironment on the lymphatic system, particularly lymphangiogenesis. It serves as a promising therapeutic target for IBD management and treatment. The interaction with gut microbiota is also explored. Main text Evidence shows that cells of the innate and adaptive immune system and certain non-immune cells participate in the complex processes of inflammatory-induced lymphangiogenesis through the secretion of a wide spectrum of molecular factors, which vary greatly among the various cells. Lymphangiogenesis enhances lymphatic fluid drainage, hence reduced infiltration of immunomodulatory cells and associated-inflammatory cytokines. Interestingly, some of the cellular mediators, including mast cells, neutrophils, basophils, monocytes, and lymphatic endothelial cells (LECs), are a source of lymphangiogenic molecules, and a target as they express specific receptors for lymphangiogenic factors. Conclusion The effective target of lymphangiogenesis is expected to provide novel therapeutic interventions for intestinal inflammatory conditions, including IBD, through both immune and non-immune cells and based on cellular and molecular mechanisms of lymphangiogenesis that facilitate inflammation resolution.
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Affiliation(s)
- Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People's Republic of China.,Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
| | - Bing Pei
- Department of Clinical Laboratory, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, 223800, Jiangsu, People's Republic of China
| | - Xinwei Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People's Republic of China
| | - Lu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People's Republic of China
| | - Chinasa Valerie Olovo
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People's Republic of China.,Department of Microbiology, University of Nigeria, Nsukka, 410001, Nigeria
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People's Republic of China.
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Shi YJ, Gong HF, Zhao QQ, Liu XS, Liu C, Wang H. Critical role of toll-like receptor 4 (TLR4) in dextran sulfate sodium (DSS)-Induced intestinal injury and repair. Toxicol Lett 2019; 315:23-30. [PMID: 31442584 DOI: 10.1016/j.toxlet.2019.08.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 07/10/2019] [Accepted: 08/19/2019] [Indexed: 12/15/2022]
Abstract
Ulcerative colitis2 (UC) is an inflammatory bowel disease3 (IBD) that causes long-lasting inflammation and ulcers in the human digestive tract. The repair function of TLR4 in the intestinal epithelium is still unknown. Here, wild-type4 (WT) mice, TLR4-knockout mice5 (KO; TLR4-/-) and commensal-depleted mice were used as dextran sulfate sodium6 (DSS)-induced or radiation-induced colitis and injury models to explore the role of TLR4 signaling in intestinal injury. Exogenous lipopolysaccharide7 (LPS) promoted DSS-induced inflammatory cytokines and aggravated intestinal damage. TLR4 deficiency and commensal bacterial depletion inhibited the toxic effects of LPS, but these mice were more susceptible to DSS-induced and radiation-induced intestinal damage. Compared with WT mice, neither DSS nor radiation promoted production of more inflammatory cytokines in the guts of TLR4-KO and commensal-depleted mice. Introducing the cytokine repair factors, PGE2 and GM-CSF, increased the cytokine levels in the guts of DSS-induced colitis mice. We hypothesized that TLR4 and its ligands repaired the epithelium after DSS-induced and radiation-induced intestinal damage by upregulating PGE2 and GM-CSF. Transwell migration assays suggested that LPS, IL6, TNF, PGE2 and GM-CSF promoted intestinal cell migration, and cell viability analysis suggested that these factors protected against radiation-induced intestinal damage. Our data underscore the importance of the balancing role of TLR4 in intestinal injury and repair.
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Affiliation(s)
- Yun-Jie Shi
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Hai-Feng Gong
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Quan-Quan Zhao
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Xiao-Shuang Liu
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Cong Liu
- Department of Radiation Medicine, Faculty of Naval Medicine, Second Military Medical University, 200433, Shanghai, China.
| | - Hao Wang
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China.
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