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Cammisa I, Rigante D, Cipolla C. A Theoretical Link Between the GH/IGF-1 Axis and Cytokine Family in Children: Current Knowledge and Future Perspectives. CHILDREN (BASEL, SWITZERLAND) 2025; 12:495. [PMID: 40310145 PMCID: PMC12026182 DOI: 10.3390/children12040495] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/09/2025] [Accepted: 04/10/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND/OBJECTIVES Growth in childhood and adolescence is influenced by a complex interaction of genetic, environmental, and hormonal factors, with growth hormone (GH) and insulin-like growth factor 1 (IGF-1) playing crucial roles in linear growth and development. However, chronic inflammation, often detected in situations like inflammatory bowel disease and juvenile idiopathic arthritis, can significantly disrupt the GH/IGF-1 axis, causing a relevant growth impairment. METHODS We conducted a retrospective review focusing on the role of cytokines in the GH-IGF-1 axis and growth. RESULTS Inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 have been shown to contribute to GH resistance through an array of mechanisms that involve the downregulation of GH receptors and alterations in IGF-1 metabolism. This disruption negatively impacts the growth plate, particularly by impairing chondrocyte proliferation and differentiation, which are essential for proper bone elongation. This review delves into the intricate relationship among growth, chronic inflammation, and GH-IGF-1 axis, emphasizing the contribution of inflammatory cytokines in modulating GH signaling. It also highlights how cytokines can interfere with the molecular pathways that regulate skeletal growth, ultimately leading to growth disturbances in children suffering from chronic inflammatory diseases. CONCLUSIONS The findings underscore the importance of controlling inflammation in affected individuals to mitigate its detrimental effects on growth and ensure that children may reach their growth full potential.
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Affiliation(s)
- Ignazio Cammisa
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
| | - Donato Rigante
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
- Department of Life Sciences and Public Health, Università Cattolica Sacro Cuore, 20123 Rome, Italy
| | - Clelia Cipolla
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
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Zhou M, Chen Y, Jin W, Li P, Hu J, Guo X. Traditional Chinese Medicine: A Promising Treatment Option for Intestinal Fibrosis. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:2107-2129. [PMID: 39581857 DOI: 10.1142/s0192415x24500812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2024]
Abstract
Intestinal fibrosis, a common complication of inflammatory bowel disease, in particular in Crohn's disease, arises from chronic inflammation, leading to intestinal narrowing, structural damage, and functional impairment that significantly impact patients' quality of life. Current treatment options for intestinal fibrosis are limited, with surgery being the primary intervention. Traditional Chinese Medicine (TCM) has emerged as a promising approach in preventing and treating intestinal fibrosis. However, there is a scarcity of literature summarizing the mechanisms underlying TCM's efficacy in this context. To address this gap, we conducted a comprehensive review, uncovering multiple mechanisms through which TCM mitigates intestinal fibrosis. These mechanisms include immune cell balance regulation, suppression of inflammatory responses, reduction of inflammatory mediators, alleviation of colon tissue damage, restoration of intestinal function, modulation of growth factors to inhibit fibroblast activation, dynamic regulation of TIMPs and MMPs to reduce extracellular matrix deposition, inhibition of epithelial-mesenchymal transition and endothelial-mesenchymal transition, autophagy modulation, maintenance of the intestinal mucosal barrier, prevention of tissue damage by harmful factors, and regulation of cell proliferation and apoptosis. This study aims to bridge existing knowledge gaps by presenting recent evidence supporting the utilization of TCM in both clinical and experimental research settings.
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Affiliation(s)
- Meng'en Zhou
- Department of Anorectal, Shanghai Municipal, Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Yan Chen
- Department of Anorectal, Shanghai Municipal, Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Wenqi Jin
- Department of Anorectal, Shanghai Municipal, Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Peng Li
- Department of Anorectal, Shanghai Municipal, Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Jie Hu
- Department of Anorectal, Shanghai Municipal, Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Xiutian Guo
- Department of Anorectal, Shanghai Municipal, Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
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Tran MT. Identification of TIMP1-induced dysregulation of epithelial-mesenchymal transition as a key pathway in inflammatory bowel disease and small intestinal neuroendocrine tumors shared pathogenesis. Front Genet 2024; 15:1376123. [PMID: 39233736 PMCID: PMC11371700 DOI: 10.3389/fgene.2024.1376123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 07/29/2024] [Indexed: 09/06/2024] Open
Abstract
Inflammatory Bowel Disease (IBD) is believed to be a risk factor for Small Intestinal Neuroendocrine Tumors (SI-NET) development; however, the molecular relationship between IBD and SI-NET has yet to be elucidated. In this study, we use a systems biology approach to uncover such relationships. We identified a more similar transcriptomic-wide expression pattern between Crohn's Disease (CD) and SI-NET whereas a higher proportion of overlapping dysregulated genes between Ulcerative Colitis (UC) and SI-NET. Enrichment analysis indicates that extracellular matrix remodeling, particularly in epithelial-mesenchymal transition and intestinal fibrosis mediated by TIMP1, is the most significantly dysregulated pathway among upregulated genes shared between both IBD subtypes and SI-NET. However, this remodeling occurs through distinct regulatory molecular mechanisms unique to each IBD subtype. Specifically, myofibroblast activation in CD and SI-NET is mediated through IL-6 and ciliary-dependent signaling pathways. Contrarily, in UC and SI-NET, this phenomenon is mainly regulated through immune cells like macrophages and the NCAM signaling pathway, a potential gut-brain axis in the context of these two diseases. In both IBD and SI-NET, intestinal fibrosis resulted in significant metabolic reprogramming of fatty acid and glucose to an inflammatory- and cancer-inducing state. This altered metabolic state, revealed through enrichment analysis of downregulated genes, showed dysfunctions in oxidative phosphorylation, gluconeogenesis, and glycogenesis, indicating a shift towards glycolysis. Also known as the Warburg effect, this glycolytic switch, in return, exacerbates fibrosis. Corresponding to enrichment analysis results, network construction and subsequent topological analysis pinpointed 7 protein complexes, 17 hub genes, 11 microRNA, and 1 transcription factor related to extracellular matrix accumulation and metabolic reprogramming that are candidate biomarkers in both IBD and SI-NET. Together, these biological pathways and candidate biomarkers may serve as potential therapeutic targets for these diseases.
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Wang X, Gu X, Liu F. IL-6 gene polymorphism predicts PEGylated IFN-α treatment response in hepatitis B surface antigen-positive chronic hepatitis B patients. Per Med 2023; 20:503-510. [PMID: 37909375 DOI: 10.2217/pme-2023-0089] [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] [Indexed: 11/03/2023]
Abstract
Background: Genetic polymorphism can affect the response to antiviral therapy of chronic hepatitis B (CHB) patients. Objective: The study examined the genetic association of the IL-6 rs1800796 polymorphism with PEGylated IFN-α (PegIFN-α) treatment response in hepatitis B surface antigen (HBsAg)-positive CHB patients. Methods: Direct sequencing was done for the genotyping of the rs1800796 polymorphism in the serum of CHB patients. Results: More patients with combined response (n = 95) carried IL-6 rs1800796 GC genotypes, while CC genotype carriers possessed reduced HBeAg seroconversion rate and high values of hepatitis B virus DNA. Baseline HBsAg and HBeAg and IL-6 rs1800796 CC genotype were independently related to PegIFN-α treatment response. Conclusion: Detection of the IL-6 rs1800796 genotype in CHB patients may have potential guiding significance for PegIFN-α response.
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Affiliation(s)
- Xiaoqing Wang
- Department of Hepatology, Shandong Provincial Third Hospital, Shandong University, Jinan, 250031, China
| | - Xiu Gu
- Department of Hepatology, Shandong Provincial Third Hospital, Shandong University, Jinan, 250031, China
| | - Fengli Liu
- Department of Gastroenterology, Shandong Provincial Third Hospital, Shandong University, Jinan, 250031, China
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A CAF-Fueled TIMP-1/CD63/ITGB1/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells. Cancers (Basel) 2022; 14:cancers14204983. [PMID: 36291767 PMCID: PMC9599197 DOI: 10.3390/cancers14204983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/04/2022] [Accepted: 10/09/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Carcinoma-associated fibroblasts (CAFs) are a major cellular component of the tumor microenvironment and influence cancer cell behavior in numerous ways. A large part of their actions is based on their high secretory activity, leading to the exposure of cancer cells to all kinds of bioactive factors, such as interleukin-6 (IL-6). Here, we present data showing that CAF-derived TIMP-1 activates STAT3 in breast cancer cells in cooperation with CD63 and integrin β1. In turn, STAT3 increases TIMP-1 secretion by breast cancer cells, leading to a TIMP-1/CD63/integrin β1/STAT3 positive feedback loop, which can be further fueled by IL-6. Functionally, this feedback loop is important for the CAF-induced increase in migratory activity and for CAF-induced resistance to the anti-estrogen fulvestrant. Abstract TIMP-1 is one of the many factors that CAFs have been shown to secret. TIMP-1 can act in a tumor-supportive or tumor-suppressive manner. The purpose of this study was to elucidate the role of CAF-secreted TIMP-1 for the effects of CAFs on breast cancer cell behavior. Breast cancer cells were exposed to conditioned medium collected from TIMP-1-secreting CAFs (CAF-CM), and the specific effects of TIMP-1 on protein expression, migration and growth were examined using TIMP-1-specifc siRNA (siTIMP1), recombinant TIMP-1 protein (rhTIMP-1) and TIMP-1 level-rising phorbol ester. We observed that TIMP-1 increased the expression of its binding partner CD63 and induced STAT3 and ERK1/2 activation by cooperating with CD63 and integrin β1. Since TIMP-1 expression was found to be dependent on STAT3, TIMP-1 activated its own expression, resulting in a TIMP-1/CD63/integrin β1/STAT3 feedback loop. IL-6, a classical STAT3 activator, further fueled this loop. Knock-down of each component of the feedback loop prevented the CAF-induced increase in migratory activity and inhibited cellular growth in adherent cultures in the presence and absence of the anti-estrogen fulvestrant. These data show that TIMP-1/CD63/integrin β1/STAT3 plays a role in the effects of CAFs on breast cancer cell behavior.
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Ezaouine A, Salam MR, Nouadi B, Anachad O, Messal ME, Chegdani F, Bennis F. In Silico Prediction of the Bioactive Profile and Metabolites of Satureja nepeta in Diseases Related to the Excessive Production of Interleukin-6. Bioinform Biol Insights 2022; 16:11779322221115665. [PMID: 35958296 PMCID: PMC9358202 DOI: 10.1177/11779322221115665] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 07/02/2022] [Indexed: 12/02/2022] Open
Abstract
Inflammatory bowel diseases are caused by an abnormal reaction of the immune system, which becomes hyperactive because the mechanisms responsible for regulating it get out of control. For an effective immune response, many proinflammatory cytokines are secreted, particularly interleukin-6 (IL-6) keystone cytokine inflammation. Many synthetic and natural compounds targeting IL-6 have been studied. The genus Satureja of the Lamiaceae family is generally known for its many virtues, in particular anti-inflammatory properties. However, the mechanism of action is unclear. This study aims to predict the impact of characterized bioactive molecules of Moroccan Satureja nepeta in the potential control of inflammatory response mediated by IL-6 cytokine. A list of 9 previously characterized natural compounds of S. nepeta was compiled, and a list of 6 potential protein targets involved in intestinal inflammation was made. The 2 lists of natural compound-target proteins were analyzed by the STITCH software (http://stitch.embl.de/) to develop protein-compound and protein-protein interaction networks (PPINs). An ontological enrichment (GO) analysis was performed by the Clue GO plugin to evaluate the PPIN generated by STITCH; finally, the molecular docking to predict the mode underlying the anti-inflammatory effects. STITCH results revealed direct and indirect interactions of S. nepeta chemical compounds with a key protein target IL-6. The array results by ClueGO showed that most compounds involved in the regulation of several biological processes related to IL-6 such as inflammation apoptosis, cell differentiation, and metabolic regulation. The targets directly related to IL-6 have been used for molecular docking. Quercetin, catechin, and gallic acid have a strong affinity with the IL-6 receptor (respectively −7.1; −6.1; −5.3). This study strongly suggests that the bioactive compounds of S. nepeta could constitute a new therapeutic alternative in the treatment of diseases related to IL-6. However, to validate the results obtained in this work, it is necessary to explore the mechanism of action of potential bioactive molecules by experimentation.
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Affiliation(s)
- Adbelkarim Ezaouine
- Immunology and Biodiversity laboratory, Faculty of Sciences Aïn Chock, Hassan II University of Casablanca, Casablanca, Morocco
| | - Mohamed Rida Salam
- Immunology and Biodiversity laboratory, Faculty of Sciences Aïn Chock, Hassan II University of Casablanca, Casablanca, Morocco
| | - Badreddine Nouadi
- Immunology and Biodiversity laboratory, Faculty of Sciences Aïn Chock, Hassan II University of Casablanca, Casablanca, Morocco
| | - Oumaima Anachad
- Immunology and Biodiversity laboratory, Faculty of Sciences Aïn Chock, Hassan II University of Casablanca, Casablanca, Morocco
| | - Mariame El Messal
- Immunology and Biodiversity laboratory, Faculty of Sciences Aïn Chock, Hassan II University of Casablanca, Casablanca, Morocco
| | - Fatima Chegdani
- Immunology and Biodiversity laboratory, Faculty of Sciences Aïn Chock, Hassan II University of Casablanca, Casablanca, Morocco
| | - Faïza Bennis
- Immunology and Biodiversity laboratory, Faculty of Sciences Aïn Chock, Hassan II University of Casablanca, Casablanca, Morocco
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Andriano TM, Benesh G, Babbush KM, Hosgood HD, Lin J, Cohen SR. Serum inflammatory markers and leukocyte profiles accurately describe hidradenitis suppurativa disease severity. Int J Dermatol 2022; 61:1270-1275. [PMID: 35543428 DOI: 10.1111/ijd.16244] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/28/2022] [Accepted: 04/19/2022] [Indexed: 01/08/2023]
Abstract
BACKGROUND Inflammatory markers and leukocyte profiles have not been longitudinally evaluated as objective signs of hidradenitis suppurativa (HS) severity. We sought to assess C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), and leukocyte profiles as reliable indicators of HS severity. METHODS Retrospective cohort study of 404 patients seen at the Einstein/Montefiore HS Center, Bronx, New York, between March 2019 and November 2020. Associations of disease severity (HS-Physician Global Assessment) with inflammatory markers and leukocyte profiles were assessed by odds ratios (OR) and 95% confidence intervals (95% CI) incorporating up to four visits per patient, adjusting for baseline gender, age, BMI, and smoking status. RESULTS Patients with severe disease had elevated CRP (OR 1.87; 95% CI 1.49, 2.34), ESR (OR 1.04; 95% CI 1.03, 1.04), IL-6 (OR 1.08; 95% CI 1.00, 1.16), leukocytes (OR 1.22; 95% CI 1.14, 1.31), neutrophils (OR 1.31; 95% CI 1.20, 1.42), eosinophils (OR 14.40; 95% CI 2.97, 69.74), basophils (OR 2.53; 95% CI 1.09, 5.85), monocytes (OR 5.36; 95% CI 2.49, 11.53), and neutrophil-lymphocyte ratios (OR 1.63; 95% CI 1.35, 1.96) but decreased lymphocytes (OR 0.86; 95% CI 0.68, 1.10). CONCLUSIONS This novel longitudinal study of inflammatory markers and leukocyte profiles offers critical laboratory measures to confirm clinically determined disease severity over time.
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Affiliation(s)
- Tyler M Andriano
- Division of Dermatology, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA
| | - Gabrielle Benesh
- Division of Dermatology, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA
| | - Kayla M Babbush
- Division of Dermatology, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA
| | - H Dean Hosgood
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Juan Lin
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Steven R Cohen
- Division of Dermatology, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA
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Singh BP, Marshall JL, He AR. Workup and Management of Immune-Mediated Colitis in Patients Treated with Immune Checkpoint Inhibitors. Oncologist 2020; 25:197-202. [PMID: 32162824 PMCID: PMC7066712 DOI: 10.1634/theoncologist.2018-0304] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/19/2019] [Indexed: 12/14/2022] Open
Abstract
As the use of immune checkpoint inhibitors for several different malignancies becomes more mainstream, their side-effect profile raises new challenges. In 2011, the Food and Drug Administration approved the first checkpoint inhibitor for the treatment of advanced melanoma, and since then, checkpoint inhibitors have demonstrated efficacy in many other tumor types. Given the frequent use of immune checkpoint inhibitors in a wide range of cancers today, the diagnosis and management of their immune-mediated toxicities need special attention. One of the most common is immune-mediated colitis. Workup and management of immune-mediated colitis can be challenging and is the purpose of this review. KEY POINTS: Rate of immune mediated colitis differ from different kind of immune checkpoint inhibitor treatment. To work up immune-mediated colitis, tests to rule out infectious etiologies of diarrhea, colonoscopy and abdominal image will help to differentiate immune mediated colitis from colitis from other etiology. Patients with mild colitis can be managed with supportive therapies alone, but more severe cases may require immunomodulators such as steroid. Refractory cases may require tumor necrosis factor (TNF) inhibitors, such as infliximab in addition to steroid treatment.
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Affiliation(s)
- Bhavana Pendurthi Singh
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical CenterWashingtonDCUSA
| | - John L. Marshall
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical CenterWashingtonDCUSA
| | - Aiwu Ruth He
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical CenterWashingtonDCUSA
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Effect of Loureirin B on Crohn's disease rat model induced by TNBS via IL-6/STAT3/NF-κB signaling pathway. Chin Med 2020; 15:2. [PMID: 31911815 PMCID: PMC6945620 DOI: 10.1186/s13020-019-0282-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 12/27/2019] [Indexed: 12/23/2022] Open
Abstract
Background Crohn’s disease (CD) is a chronic relapsing form of inflammatory bowel disease, seriously threatening human beings health. However, the pathogenesis of CD is still unclear and there is no specific effective drug for treatment of CD. Resina Donis (RD) obtained from Dracaena cochinchinensis (Lour.) S. C. Chen (Liliaceae), has been used for the treatment of CD clinically. Loureirin B (LB) is one of the most important chemical compositions and physiologically active ingredients of resina draconis. It has the molecular structure propan-1-one, 1-(4-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)-1-(4-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl) propan-1-one. The aim of this study was to investigate the effect of LB on CD and explore the underlying mechanisms. Methods and results In this study, the result demonstrated that LB prolonged the survival time of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rats and alleviated colonic damage in a dose dependent manner. Besides, LB remarkably ameliorated TNBS-induced inflammatory response via regulation of cytokines in the colonic tissues. Moreover, LB could reverse the established fibrosis and impede the accumulation infiltration, and improve the apoptosis induced by TNBS in a dose dependent manner. Further, LB dramatically suppressed TNBS-induced the activation of IL-6/STAT3/NF-κB signaling pathway. Conclusions These findings suggested that LB could be beneficial regarding ameliorating TNBS-induced CD, which may represent a novel approach to treat CD and provide an alternative choice for disorders associated with CD.
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10
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Li C, Shoji S, Beebe J. Pharmacokinetics and C-reactive protein modelling of anti-interleukin-6 antibody (PF-04236921) in healthy volunteers and patients with autoimmune disease. Br J Clin Pharmacol 2018; 84:2059-2074. [PMID: 29776017 DOI: 10.1111/bcp.13641] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 03/29/2018] [Accepted: 04/27/2018] [Indexed: 12/11/2022] Open
Abstract
AIMS The purpose of this study was to characterize pharmacokinetics (PK) of PF-04236921, a novel anti-interleukin-6 monoclonal antibody, and its pharmacokinetic/pharmacodynamic (PK/PD) relationship on serum C-reactive protein (CRP) in healthy volunteers and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Crohn's disease (CD). METHODS Population modelling analyses were conducted using nonlinear mixed effects modelling. Data from two phase 1 healthy volunteer studies, a phase 1 RA study, a Phase 2 CD study and a Phase 2 SLE study were included. RESULTS A two-compartment model with first order absorption and linear elimination and a mechanism-based indirect response model adequately described the PK and PK/PD relationships, respectively. Central compartment volume of distribution (Vc) positively correlated with body weight. Clearance (CL) negatively correlated with baseline albumin concentration and positively correlated with baseline CRP and creatinine clearance, and was slightly lower in females. After correcting for covariates, CL in CD subjects was approximately 60% higher than other populations. Maximum inhibition of PF-04236921 on CRP production (Imax ) negatively correlated with baseline albumin. Imax positively correlated with baseline CRP and the relationship was captured as a covariance structure in the PK/PD model. CONCLUSION Integrated population PK and PK/PD models of PF-04236921 have been developed using pooled data from healthy subjects and autoimmune patients. The current model enables simulation of PF-04236921 PK and PD profiles under various dosing regimens and patient populations and should facilitate future clinical study of PF-04236921 and other anti-interleukin-6 monoclonal antibodies.
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Affiliation(s)
- Cheryl Li
- Clinical Pharmacology/Pharmacometrics, Clinical Research, Pfizer Inc., Cambridge, MA, USA
| | - Satoshi Shoji
- Pharmacometrics/Clinical Pharmacology, Clinical Research, Pfizer Japan Inc., Yoyogi, Shibuya-ku, Tokyo, Japan
| | - Jean Beebe
- Clinical Research, Pfizer Inc., Cambridge, MA, USA
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11
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Lawrance IC, Rogler G, Bamias G, Breynaert C, Florholmen J, Pellino G, Reif S, Speca S, Latella G. Cellular and Molecular Mediators of Intestinal Fibrosis. J Crohns Colitis 2017. [PMID: 25306501 DOI: 10.1016/j.crohns.2014.09.00] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Intestinal fibrosis is a major complication of the inflammatory bowel diseases (IBD) and although inflammation is necessary for its development, it would appear that it plays a minor role in its progression as anti-inflammatory treatments in IBD do not prevent fibrosis once it has started. The processes that regulate fibrosis would thus appear to be distinct from those regulating inflammation and, therefore, a detailed understanding of these pathways is vital to the development of anti-fibrogenic strategies. There have been several recent reviews exploring what is known, and what remains unknown, about the development of intestinal fibrosis. This review is designed to add to this literature but with a focus on the cellular components that are involved in the development of fibrogenesis and the major molecular mediators that impact on these cells. The aim is to heighten the understanding of the factors involved in intestinal fibrogenesis so that detailed research can be encouraged in order to advance the processes that could lead to effective treatments.
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Affiliation(s)
- Ian C Lawrance
- Centre for Inflammatory Bowel Diseases, Fremantle Hospital, Fremantle, WA, Australia.,University Department of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Freemantle, WA, Australia
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| | - Giorgos Bamias
- Academic Department of Gastroenterology, Ethnikon and Kapodistriakon University of Athens, Laikon Hospital, Athens, Greece
| | - Christine Breynaert
- Department of Immunology and Microbiology, Laboratory of Clinical Immunology, KU Leuven, Leuven, Belgium.,Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Jon Florholmen
- Research Group of Gastroenterology and Nutrition, Institute of Clinical Medicine, Artic University of Norway and University Hospital of Northern Norway, Tromsø, Norway
| | - Gianluca Pellino
- General Surgery Unit, Second University of Naples, Naples, Italy
| | - Shimon Reif
- Department of Pediatrics, Tel-Aviv Souraski Medical Center, Tel-Aviv, Israel
| | - Silvia Speca
- National Institute of Health and Medical Research-INSERM, Unit U995, Lille, France
| | - Giovanni Latella
- Department of Life, Health and Environmental Sciences, Gastroenterology Unit, University of L'Aquila, L'Aquila, Italy
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12
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Lawrance IC, Rogler G, Bamias G, Breynaert C, Florholmen J, Pellino G, Reif S, Speca S, Latella G. Cellular and Molecular Mediators of Intestinal Fibrosis. J Crohns Colitis 2017; 11:1491-1503. [PMID: 25306501 PMCID: PMC5885809 DOI: 10.1016/j.crohns.2014.09.008] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Intestinal fibrosis is a major complication of the inflammatory bowel diseases (IBD) and although inflammation is necessary for its development, it would appear that it plays a minor role in its progression as anti-inflammatory treatments in IBD do not prevent fibrosis once it has started. The processes that regulate fibrosis would thus appear to be distinct from those regulating inflammation and, therefore, a detailed understanding of these pathways is vital to the development of anti-fibrogenic strategies. There have been several recent reviews exploring what is known, and what remains unknown, about the development of intestinal fibrosis. This review is designed to add to this literature but with a focus on the cellular components that are involved in the development of fibrogenesis and the major molecular mediators that impact on these cells. The aim is to heighten the understanding of the factors involved in intestinal fibrogenesis so that detailed research can be encouraged in order to advance the processes that could lead to effective treatments.
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Affiliation(s)
- Ian C Lawrance
- Centre for Inflammatory Bowel Diseases, Fremantle Hospital, Fremantle, WA, Australia
- University Department of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Freemantle, WA, Australia
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| | - Giorgos Bamias
- Academic Department of Gastroenterology, Ethnikon and Kapodistriakon University of Athens, Laikon Hospital, Athens, Greece
| | - Christine Breynaert
- Department of Immunology and Microbiology, Laboratory of Clinical Immunology, KU Leuven, Leuven, Belgium
- Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Jon Florholmen
- Research Group of Gastroenterology and Nutrition, Institute of Clinical Medicine, Artic University of Norway and University Hospital of Northern Norway, Tromsø, Norway
| | - Gianluca Pellino
- General Surgery Unit, Second University of Naples, Naples, Italy
| | - Shimon Reif
- Department of Pediatrics, Tel-Aviv Souraski Medical Center, Tel-Aviv, Israel
| | - Silvia Speca
- National Institute of Health and Medical Research-INSERM, Unit U995, Lille, France
| | - Giovanni Latella
- Department of Life, Health and Environmental Sciences, Gastroenterology Unit, University of L’Aquila, L’Aquila, Italy
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Sobotta S, Raue A, Huang X, Vanlier J, Jünger A, Bohl S, Albrecht U, Hahnel MJ, Wolf S, Mueller NS, D'Alessandro LA, Mueller-Bohl S, Boehm ME, Lucarelli P, Bonefas S, Damm G, Seehofer D, Lehmann WD, Rose-John S, van der Hoeven F, Gretz N, Theis FJ, Ehlting C, Bode JG, Timmer J, Schilling M, Klingmüller U. Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib. Front Physiol 2017; 8:775. [PMID: 29062282 PMCID: PMC5640784 DOI: 10.3389/fphys.2017.00775] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 09/22/2017] [Indexed: 12/12/2022] Open
Abstract
IL-6 is a central mediator of the immediate induction of hepatic acute phase proteins (APP) in the liver during infection and after injury, but increased IL-6 activity has been associated with multiple pathological conditions. In hepatocytes, IL-6 activates JAK1-STAT3 signaling that induces the negative feedback regulator SOCS3 and expression of APPs. While different inhibitors of IL-6-induced JAK1-STAT3-signaling have been developed, understanding their precise impact on signaling dynamics requires a systems biology approach. Here we present a mathematical model of IL-6-induced JAK1-STAT3 signaling that quantitatively links physiological IL-6 concentrations to the dynamics of IL-6-induced signal transduction and expression of target genes in hepatocytes. The mathematical model consists of coupled ordinary differential equations (ODE) and the model parameters were estimated by a maximum likelihood approach, whereas identifiability of the dynamic model parameters was ensured by the Profile Likelihood. Using model simulations coupled with experimental validation we could optimize the long-term impact of the JAK-inhibitor Ruxolitinib, a therapeutic compound that is quickly metabolized. Model-predicted doses and timing of treatments helps to improve the reduction of inflammatory APP gene expression in primary mouse hepatocytes close to levels observed during regenerative conditions. The concept of improved efficacy of the inhibitor through multiple treatments at optimized time intervals was confirmed in primary human hepatocytes. Thus, combining quantitative data generation with mathematical modeling suggests that repetitive treatment with Ruxolitinib is required to effectively target excessive inflammatory responses without exceeding doses recommended by the clinical guidelines.
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Affiliation(s)
- Svantje Sobotta
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
| | - Andreas Raue
- Discovery Division, Merrimack Pharmaceuticals, Cambridge, MA, United States
| | - Xiaoyun Huang
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
| | - Joep Vanlier
- Institute of Physics, Albert Ludwigs University of Freiburg, Freiburg, Germany.,BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - Anja Jünger
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
| | - Sebastian Bohl
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
| | - Ute Albrecht
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
| | - Maximilian J Hahnel
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
| | - Stephanie Wolf
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
| | - Nikola S Mueller
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Lorenza A D'Alessandro
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
| | - Stephanie Mueller-Bohl
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
| | - Martin E Boehm
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
| | - Philippe Lucarelli
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
| | - Sandra Bonefas
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, Leipzig University, Leipzig, Germany
| | - Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral Transplantation, Leipzig University, Leipzig, Germany
| | - Wolf D Lehmann
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
| | | | - Frank van der Hoeven
- Transgenic Service, Center for Preclinical Research, German Cancer Research Center, Heidelberg, Germany
| | - Norbert Gretz
- Medical Research Center, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Fabian J Theis
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.,Department of Mathematics, Technical University of Munich, Garching, Germany
| | - Christian Ehlting
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
| | - Johannes G Bode
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
| | - Jens Timmer
- Institute of Physics, Albert Ludwigs University of Freiburg, Freiburg, Germany.,BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - Marcel Schilling
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
| | - Ursula Klingmüller
- Division Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany
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14
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Dekita M, Wu Z, Ni J, Zhang X, Liu Y, Yan X, Nakanishi H, Takahashi I. Cathepsin S Is Involved in Th17 Differentiation Through the Upregulation of IL-6 by Activating PAR-2 after Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis. Front Pharmacol 2017; 8:470. [PMID: 28769800 PMCID: PMC5511830 DOI: 10.3389/fphar.2017.00470] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 06/30/2017] [Indexed: 12/15/2022] Open
Abstract
Positive links have been found between periodontitis and numerous diseases in humans via persistent inflammation throughout the body. However, the main factors responsible for maintaining this pro-inflammatory condition are poorly understood. The spleen, the largest secondary immune organ, is a central hub regulating the immune response/inflammation due to the dendritic cell (DC) response to CD4+ T cell subtype differentiation, and lysosomal proteinase cathepsin S (CatS) is known to be involved in DC functions. In the present study, we found that CatS-induced IL-6 production by splenic DCs subsequently promotes Th17 differentiation, in response to systemic exposure to lipopolysaccharide derived from Porphyromonas gingivalis (PgLPS). The population of CD11c+ DCs was significantly increased in the splenic marginal zone (MZ) locally of wild-type (DBA/2) mice with splenomegaly but not in that of CatS deficient (CatS-/-) mice after systemic exposure to PgLPS for 7 consecutive days (5 mg/kg/day, intraperitoneal). Similarly, the population of Th17+CD4+ T cells was also significantly increased in the splenic MZ of wild-type mice but not in that of CatS-/- mice after PgLPS exposure. Furthermore, the increase in the Th17+ CD4+ T cell population paralleled increases in the levels of CatS and IL-6 in CD11c+ cells in the splenic MZ. In isolated primary splenic CD11c+ cells, the mRNA expression and the production of IL-6 was dramatically increased in wild-type mice but not in CatS-/- mice after direct stimulation with PgLPS (1 μg/ml), and this PgLPS-induced increase in the IL-6 expression was completely abolished by pre-treatment with Z-Phe-Leu-COCHO (Z-FL), the specific inhibitor of CatS. The PgLPS activated protease-activated receptor (PAR) 2 in the isolated splenic CD11c+ cells was also significantly inhibited by CatS deficiently. In addition, the PgLPS-induced increase in the IL-6 production by splenic CD11c+ cells was completely abolished by pre-treatment with FSLLRY-NH2, a PAR2 antagonist, as well as Akti, a specific inhibitor of Akt. These findings indicate that CatS plays a critical role in driving splenic DC-dependent Th17 differentiation through the upregulation of IL-6 by activating PAR2 after exposure to components of periodontal bacteria. Therefore, CatS-specific inhibitors may be effective in alleviating periodontitis-related immune/inflammation.
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Affiliation(s)
- Masato Dekita
- Section of Orthodontics and Dentofacial Orthopedics, Kyushu UniversityFukuoka, Japan
| | - Zhou Wu
- Department of Aging Science and Pharmacology, Kyushu UniversityFukuoka, Japan.,OBT Research Center, Faculty of Dental Science, Kyushu UniversityFukuoka, Japan
| | - Junjun Ni
- Department of Aging Science and Pharmacology, Kyushu UniversityFukuoka, Japan
| | - Xinwen Zhang
- Department of Aging Science and Pharmacology, Kyushu UniversityFukuoka, Japan.,Center of Implant Dentistry, School of Stomatology, China Medical UniversityShenyang, China
| | - Yicong Liu
- Department of Aging Science and Pharmacology, Kyushu UniversityFukuoka, Japan
| | - Xu Yan
- The VIP Department, School of Stomatology, China Medical UniversityShenyang, China
| | - Hiroshi Nakanishi
- Department of Aging Science and Pharmacology, Kyushu UniversityFukuoka, Japan
| | - Ichiro Takahashi
- Section of Orthodontics and Dentofacial Orthopedics, Kyushu UniversityFukuoka, Japan
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15
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The emerging role of signal transducer and activator of transcription 3 in cerebral ischemic and hemorrhagic stroke. Prog Neurobiol 2016; 137:1-16. [DOI: 10.1016/j.pneurobio.2015.11.001] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 10/13/2015] [Accepted: 11/18/2015] [Indexed: 01/05/2023]
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16
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Eder P, Łykowska-Szuber L, Krela-Kaźmierczak I, Stawczyk-Eder K, Iwanik K, Majewski P, Sterzyńska K, Zabel M, Linke K. Disturbances in apoptosis of lamina propria lymphocytes in Crohn's disease. Arch Med Sci 2015; 11:1279-85. [PMID: 26788091 PMCID: PMC4697047 DOI: 10.5114/aoms.2015.54203] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 10/04/2013] [Indexed: 01/01/2023] Open
Abstract
INTRODUCTION The aim of this study was to assess the potential mechanisms providing resistance to apoptosis of lamina propria lymphocytes (LPL) directlyin intestinal tissues from patients with Crohn's disease (CD). MATERIAL AND METHODS Fifty CD patients were enrolled in the study. The control group consisted of healthy patients who underwent surveillance colonoscopy after endoscopic polypectomy. Each CD patient underwent colonoscopy with tissue sampling from inflamed areas of the colon with the assessment of immunohistochemical expression of active caspase 3, Fas, tumour necrosis factor receptor 1 (TNFR1), Bcl-2, Bax, CD4 and CD8. This was compared with healthy intestinal mucosa. RESULTS The expression of active caspase 3 was significantly lower in LPL in CD (0.4 ±0.3 vs. 2.8 ±1.5; p = 0.0002). A statistically significant increase of CD4 and CD8 positive cells was noted in CD (2.3 ±0.5 vs. 1.2 ±0.2, p < 0.0001; 2.1 ±0.3 vs. 1.1 ±0.3, p < 0.0001, respectively). It was associated with a significant increase of the Bcl-2 (6.7 ±2.7 vs. 2.9 ±0.8; p < 0.0001) and a decrease of the Bax protein expression (3.4 ±2.1 vs. 5.5 ±1.8; p < 0.0001) in CD. The expression of Fas and TNFR1 did not differ between the study groups. CONCLUSIONS LPL in CD are resistant to apoptosis when compared with physiological conditions. This is probably due to an imbalance in Bcl-2 family proteins. TNFR1-related pathway is probably not involved in disturbances of LPL apoptosis in CD.
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Affiliation(s)
- Piotr Eder
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Liliana Łykowska-Szuber
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Iwona Krela-Kaźmierczak
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Kamila Stawczyk-Eder
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Katarzyna Iwanik
- Department of Clinical Pathomorphology, Poznan University of Medical Sciences, Poznan, Poland
| | - Przemysław Majewski
- Department of Clinical Pathomorphology, Poznan University of Medical Sciences, Poznan, Poland
| | - Karolina Sterzyńska
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland
| | - Maciej Zabel
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland
| | - Krzysztof Linke
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
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Involvement of pro-inflammatory cytokines and growth factors in the pathogenesis of Dupuytren's contracture: a novel target for a possible future therapeutic strategy? Clin Sci (Lond) 2015. [PMID: 26201022 DOI: 10.1042/cs20150088] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Dupuytren's contracture (DC) is a benign fibro-proliferative disease of the hand causing fibrotic nodules and fascial cords which determine debilitating contracture and deformities of fingers and hands. The present study was designed to characterize pro-inflammatory cytokines and growth factors involved in the pathogenesis, progression and recurrence of this disease, in order to find novel targets for alternative therapies and strategies in controlling DC. The expression of pro-inflammatory cytokines and of growth factors was detected by immunohistochemistry in fibrotic nodules and normal palmar fascia resected respectively from patients affected by DC and carpal tunnel syndrome (CTS; as negative controls). Reverse transcription (RT)-PCR analysis and immunofluorescence were performed to quantify the expression of transforming growth factor (TGF)-β1, interleukin (IL)-1β and vascular endothelial growth factor (VEGF) by primary cultures of myofibroblasts and fibroblasts isolated from Dupuytren's nodules. Histological analysis showed high cellularity and high proliferation rate in Dupuytren's tissue, together with the presence of myofibroblastic isotypes; immunohistochemical staining for macrophages was completely negative. In addition, a strong expression of TGF-β1, IL-1β and VEGF was evident in the extracellular matrix and in the cytoplasm of fibroblasts and myofibroblasts in Dupuytren's nodular tissues, as compared with control tissues. These results were confirmed by RT-PCR and by immunofluorescence in pathological and normal primary cell cultures. These preliminary observations suggest that TGF-β1, IL-1β and VEGF may be considered potential therapeutic targets in the treatment of Dupuytren's disease (DD).
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18
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Ding H, Gan HZ, Fan WJ, Cao LY, Xu JM, Mei Q. Homocysteine promotes intestinal fibrosis in rats with trinitrobenzene sulfonic acid-induced colitis. Dig Dis Sci 2015; 60:375-381. [PMID: 25293822 DOI: 10.1007/s10620-014-3379-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 09/26/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Previous studies have revealed significantly increased levels of plasma and mucosal homocysteine (Hcy) in patients with Crohn's disease (CD); however, whether Hcy is involved in intestinal fibrosis of CD remains unclear. This study aimed to investigate the effects of Hcy on intestinal fibrosis in TNBS/ethanol-induced colitis and to elucidate its potential mechanisms. METHODS Sprague-Dawley rats were divided into 4 groups: normal control, normal + Hcy injection, TNBS model and TNBS model + Hcy injection. Hyperhomocysteinemia was induced by subcutaneous injection of Hcy. DAI, CMDI and HI were calculated to evaluate the severity of colitis. Masson trichrome staining was performed to assess the severity of fibrosis. The plasma and mucosal levels of Hcy were measured by HPLC-FD. The levels of IL-1β, IL-6, TNF-α, TGF-β1, CTGF, MMP-2,9 and collagen I, III in the colon were determined by ELISA, and the mRNA expressions of TGF-β1, MMP-2,9 and TIMP-1 were detected by RT-PCR. RESULTS Hcy was found to increase the scores of DAI, CMDI and HI; levels of IL-1β, Il-6, TNF-α, TGF-β1, CTGF, MMP-2,9 and collagen I, III; and mRNA expressions of TGF-β1, MMP-2,9 and TIMP-1 in colonic tissue of rats with TNBS/ethanol-induced colitis. CONCLUSIONS Hcy promotes intestinal fibrosis in rats with TNBS/ethanol-induced colitis, the underlying mechanisms of which may be attributed to its effects of increasing inflammatory damage, promoting the expression of profibrogenic cytokines and influencing MMPs/TIMPs balance.
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Affiliation(s)
- Hao Ding
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China,
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19
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Pattanshetty DJ, Anna K, Gajulapalli RD, Sappati-Biyyani RR. Inflammatory bowel "Cardiac" disease: Point prevalence of atrial fibrillation in inflammatory bowel disease population. Saudi J Gastroenterol 2015; 21:325-9. [PMID: 26458861 PMCID: PMC4632259 DOI: 10.4103/1319-3767.166208] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND/AIM Proinflammatory markers such as interleukin (IL)-6 have been closely associated with atrial fibrillation (AF). These markers are characteristically elevated in chronic inflammatory bowel disease (IBD) and positively correlate with disease activity. Although IBD and AF have similar pathogenesis, there have been very limited studies looking at their association. The aim of this study is to determine the prevalence of AF in patients with IBD. PATIENTS AND METHODS Medical records of patients with biopsy proven IBD (n = 203, both in and outpatient) were retrospectively reviewed. One hundred and forty-one IBD patients with documentary evidence of electrocardiograms (ECG's) were included. The "Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA)" study, a large cross-sectional study (n = 1.89 million) done to evaluate the prevalence of AF among the US population, was our control population. All ECGs available till December 2010 for each IBD patient were reviewed carefully for evidence of AF. We studied the prevalence of AF among IBD population and compared it to that of control (ATRIA) population. RESULTS The prevalence of AF was significantly higher among IBD patients compared with the ATRIA study patients (11.3% vs 0.9%, P < 0.0001). Additionally, the IBD patient population were much younger compared with the controls (64.4 ± 10.7 vs 71.2 ± 12.2, P = 0.02). CONCLUSION AF has an overall higher prevalence across all age groups in IBD compared with the subjects of ATRIA study, which could be due to the chronic inflammatory state of IBD. Further studies are needed to study the association in detail.
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Affiliation(s)
- Deepak J. Pattanshetty
- Department of Heart and Vascular Center, MetroHealth Campus of Case Western Reserve University, Cleveland, Ohio, USA,Address for correspondence: Dr. Deepak J. Pattanshetty, Department of Cardiology, MetroHealth, 2500 MetroHealth Drive, Cleveland, OH 44109, USA. E-mail:
| | - Kiran Anna
- Department of Gastroenterology, MetroHealth Campus of Case Western Reserve University, Cleveland, Ohio, USA
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Alterations in programmed cell death mechanism and their role in the pathogenesis of inflammatory bowel diseases. GASTROENTEROLOGY REVIEW 2014; 9:275-9. [PMID: 25396001 PMCID: PMC4223115 DOI: 10.5114/pg.2014.46162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/04/2012] [Revised: 09/15/2012] [Accepted: 11/25/2012] [Indexed: 01/28/2023]
Abstract
Apoptosis plays an essential role in both physiology and pathology. In the pathogenesis of inflammatory bowel diseases, disturbances of apoptosis also play an important role. Inflammatory cells (for example lymphocytes, granulocytes) in the gut wall are resistant to apoptotic stimuli and they accumulate there causing tissue damage. On the other hand, apoptotic elimination of the enterocytes is enhanced, which leads to the impairment of the gut barrier. The exact mechanisms of these phenomena are still poorly understood and they are still under investigation. The present paper summarises current knowledge in terms of the role of alterations of programmed cell death in the pathogenesis of inflammatory bowel diseases.
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Bettenworth D, Rieder F. Medical therapy of stricturing Crohn's disease: what the gut can learn from other organs - a systematic review. FIBROGENESIS & TISSUE REPAIR 2014; 7:5. [PMID: 24678903 PMCID: PMC4230721 DOI: 10.1186/1755-1536-7-5] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 03/06/2014] [Indexed: 12/11/2022]
Abstract
Crohn’s disease (CD) is a chronic remitting and relapsing disease. Fibrostenosing complications such as intestinal strictures, stenosis and ultimately obstruction are some of its most common long-term complications. Despite recent advances in the pathophysiological understanding of CD and a significant improvement of anti-inflammatory therapeutics, medical therapy for stricturing CD is still inadequate. No specific anti-fibrotic therapy exists and the incidence rate of strictures has essentially remained unchanged. Therefore, the current therapy of established fibrotic strictures comprises mainly endoscopic dilation as well as surgical approaches. However, these treatment options are associated with major complications as well as high recurrence rates. Thus, a specific anti-fibrotic therapy for CD is urgently needed. Importantly, there is now a growing body of evidence for prevention as well as effective medical treatment of fibrotic diseases of other organs such as the skin, lung, kidney and liver. In face of the similarity of molecular mechanisms of fibrogenesis across these organs, translation of therapeutic approaches from other fibrotic diseases to the intestine appears to be a promising treatment strategy. In particular transforming growth factor beta (TGF-β) neutralization, selective tyrosine kinase inhibitors, blockade of components of the renin-angiotensin system, IL-13 inhibitors and mammalian target of rapamycin (mTOR) inhibitors have emerged as potential drug candidates for anti-fibrotic therapy and may retard progression or even reverse established intestinal fibrosis. However, major challenges have to be overcome in the translation of novel anti-fibrotics into intestinal fibrosis therapy, such as the development of appropriate biomarkers that predict the development and accurately monitor therapeutic responses. Future clinical studies are a prerequisite to evaluate the optimal timing for anti-fibrotic treatment approaches, to elucidate the best routes of application, and to evaluate the potential of drug candidates to reach the ultimate goal: the prevention or reversal of established fibrosis and strictures in CD patients.
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Affiliation(s)
| | - Florian Rieder
- Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.,Department of Pathobiology, Lerner Research Institute, NC22, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
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22
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The influence of infliximab and adalimumab on the expression of apoptosis-related proteins in lamina propria mononuclear cells and enterocytes in Crohn's disease - an immunohistochemical study. J Crohns Colitis 2013; 7:706-16. [PMID: 23021876 DOI: 10.1016/j.crohns.2012.09.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Revised: 08/30/2012] [Accepted: 09/05/2012] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS The aim of this study was to assess the influence of anti-TNF agents on the expression of apoptosis-related proteins in Crohn's disease (CD) patients. METHODS The clinical, biochemical and endoscopic activity of CD was assessed with the use of tissue sampling before the initiation of therapy and after induction doses of infliximab and adalimumab. Additionally, the immunohistochemical expression of active caspase 3, TNFR1, Fas, Bcl-2, Bax, CD4 and CD8 proteins was estimated. Patients achieving deep remission were considered as responders. RESULTS Of the 35 patients qualified for the study, 60% achieved deep remission. In those patients, a significant decrease in the number of CD4 and CD8 positive cells was noted. Also observed was a significant increase in the expression of active caspase 3 in lamina propria mononuclear cells, which correlated with an increase of the pro-apoptotic Bax/Bcl-2 ratio. No change in Fas and TNFR1 expression was observed in those cells. Moreover, there was a significant decrease in active caspase 3 expression in enterocytes, observed independently of the Bax/Bcl-2 ratio. This correlated with a change in TNFR1 expression. No significant changes in the expression of the investigated proteins were noted in non-responders group. CONCLUSIONS The efficacy of anti-TNF antibodies is, at least partly, dependent on apoptosis modulation. In lamina propria mononuclear cells, the increase of apoptosis is probably the result of the induction of the intrinsic pathway mediated by Bcl-2 family proteins. In enterocytes - the decrease of apoptosis is mediated by the extrinsic pathway, probably via TNFR1.
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Lahdou I, Sadeghi M, Oweira H, Fusch G, Daniel V, Mehrabi A, Jung GE, Elhadedy H, Schmidt J, Sandra-Petrescu F, Iancu M, Opelz G, Terness P, Schefold JC. Increased serum levels of quinolinic acid indicate enhanced severity of hepatic dysfunction in patients with liver cirrhosis. Hum Immunol 2013; 74:60-6. [DOI: 10.1016/j.humimm.2012.09.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 08/28/2012] [Accepted: 09/10/2012] [Indexed: 01/29/2023]
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Speca S, Giusti I, Rieder F, Latella G. Cellular and molecular mechanisms of intestinal fibrosis. World J Gastroenterol 2012; 18:3635-61. [PMID: 22851857 PMCID: PMC3406417 DOI: 10.3748/wjg.v18.i28.3635] [Citation(s) in RCA: 200] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 03/26/2012] [Accepted: 04/09/2012] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.
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25
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Lee JY, Park W. Anti-inflammatory effect of myristicin on RAW 264.7 macrophages stimulated with polyinosinic-polycytidylic acid. Molecules 2011; 16:7132-42. [PMID: 21991618 PMCID: PMC6264243 DOI: 10.3390/molecules16087132] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Myristicin (1-allyl-5-methoxy-3,4-methylenedioxybenzene) is an active aromatic compound found in nutmeg (the seed of Myristica fragrans), carrot, basil,cinnamon, and parsley. Myristicin has been known to have anti-cholinergic, antibacterial,and hepatoprotective effects, however, the effects of myristicin on virus-stimulated macrophages are not fully reported. In this study, the anti-inflammatory effect of myristicin on double-stranded RNA (dsRNA)-stimulated macrophages was examined. Myristicin did not reduce the cell viability of RAW 264.7 mouse macrophages at concentrations of up to 50 μM. Myristicin significantly inhibited the production of calcium, nitric oxide (NO),interleukin (IL)-6, IL-10, interferon inducible protein-10, monocyte chemotactic protein(MCP)-1, MCP-3, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein (MIP)-1α, MIP-1β, and leukemia inhibitory factor in dsRNA[polyinosinic-polycytidylic acid]-induced RAW 264.7 cells (P < 0.05). In conclusion,myristicin has anti-inflammatory properties related with its inhibition of NO, cytokines,chemokines, and growth factors in dsRNA-stimulated macrophages via the calcium pathway.
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Affiliation(s)
| | - Wansu Park
- Author to whom correspondence should be addressed; ; Tel.: +82-31-750-8821; Fax: +82-31-750-8821
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Scharl M, Hruz P, McCole DF. Protein tyrosine phosphatase non-receptor Type 2 regulates IFN-γ-induced cytokine signaling in THP-1 monocytes. Inflamm Bowel Dis 2010; 16:2055-64. [PMID: 20848498 DOI: 10.1002/ibd.21325] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND We have previously shown that the Crohn's disease (CD)-associated gene protein tyrosine phosphatase non-receptor Type 2 (PTPN2) regulates interferon gamma (IFN-γ)-induced signaling and barrier function in intestinal epithelial cells. Overactivation of immature immune cells has been demonstrated in CD and elevated levels of proinflammatory cytokines, such as IFN-γ, play an important pathophysiological role in this disease. Here we studied the role of PTPN2 in the regulation of IFN-γ-induced signaling in THP-1 monocytic cells. METHODS Protein analysis was performed by Western blotting, PTPN2 knockdown was induced by siRNA, and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS We demonstrated that IFN-γ (1000 U/mL) treatment of THP-1 cells elevates PTPN2 protein, reaching a peak by 24 hours. Increased PTPN2 expression, in turn, correlated with decreased activity of the signaling molecules, signal transducer and activator of transcription (STAT) 1 and STAT3. Loss of PTPN2 potentiated IFN-γ-induced phosphorylation of both of the STATs and of the mitogen-activated protein kinase (MAPK) family member, p38. However, PTPN2 loss did not affect the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 or c-Jun N-terminal kinase. As a functional consequence, PTPN2 knockdown elevated the IFN-γ-induced secretion of the proinflammatory cytokines interleukin-6 (IL-6) and macrophage chemoattractant protein 1 (MCP-1). CONCLUSIONS Our data demonstrate that IFN-γ enhances PTPN2 protein in THP-1 cells and loss of PTPN2 promotes IFN-γ-induced STAT signaling and secretion of IL-6 and MCP-1. Therefore, we show that PTPN2 regulates inflammation-related events and PTPN2 dysregulation may contribute to the onset as well as to the perpetuation of inflammatory events associated with CD.
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Affiliation(s)
- Michael Scharl
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California, USA
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Mohan M, Aye PP, Borda JT, Alvarez X, Lackner AA. CCAAT/enhancer binding protein beta is a major mediator of inflammation and viral replication in the gastrointestinal tract of simian immunodeficiency virus-infected rhesus macaques. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 173:106-18. [PMID: 18535173 DOI: 10.2353/ajpath.2008.080108] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The gastrointestinal tract (GIT) is a major target of infection with human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). Chronic GIT disease and inflammation are common sequelae to HIV/SIV infection. Nonetheless, the molecular mechanisms that cause and maintain GIT dysfunction remain unclear. We investigated the contribution of CCAAT/enhancer-binding protein beta (C/EBPbeta) to GIT disease and viral replication in jejunum and colon collected at necropsy from 12 SIV-infected (group 1), or 10 uninfected macaques with chronic diarrhea (group 2), and 9 uninfected control macaques (group 3). All group 1 and 2 macaques had chronic diarrhea, wasting, and colitis, but group 1 animals had more severe lesions in the jejunum. C/EBPbeta gene expression increased significantly in colon of groups 1 and 2 and in jejunum of only group 1 macaques compared with controls. In group 1 animals, CEBPbeta expression was localized predominantly to macrophages and occasionally lymphocytes. Chromatin immunoprecipitation assays confirmed the binding of C/EBPbeta and p65 to the SIV long terminal repeat region in colonic lamina propria cells, suggesting a mechanistic link between inflammation and activation of viral replication in vivo. This is the first in vivo study describing the transcriptional changes and immunophenotypic localization of C/EBPbeta in the GIT of SIV-infected macaques. More importantly, these data provide a molecular mechanism for persistent inflammation and immune activation leading to increased SIV burden and GIT pathology in SIV-infected macaques and perhaps HIV-infected individuals.
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Affiliation(s)
- Mahesh Mohan
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana 70433, USA
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28
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Song J, Matsuda C, Kai Y, Nishida T, Nakajima K, Mizushima T, Kinoshita M, Yasue T, Sawa Y, Ito T. A novel sphingosine 1-phosphate receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), regulates chronic colitis in interleukin-10 gene-deficient mice. J Pharmacol Exp Ther 2008; 324:276-83. [PMID: 17898319 DOI: 10.1124/jpet.106.119172] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Current treatments for patients with Crohn's disease (CD) are based on recent advances in elucidating the pathophysiology of the disease. A satisfactory therapeutic strategy has not been well established. A new sphingosine 1-phosphate (S1P) receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), has been developed for immunomodulation in autoimmune diseases and organ transplantation. We aimed to evaluate the efficacy and potency of KRP-203 on the treatment of chronic colitis in an interleukin (IL)-10 gene-deficient (IL-10(-/-)) mouse model. KRP-203 agonistic activity on S1P receptor was assessed in vitro. KRP-203 was administered for 1 or 4 weeks to IL-10(-/-) mice with clinical signs of colitis. The histological appearance of the colon and the numbers, phenotype, and cytokine production of lymphocytes were compared with a control group. KRP-203 treatment was effective in preventing body weight loss in the IL-10(-/-) colitis model. One-week administration resulted in the sequestration of circulating lymphocytes within the secondary lymphoid tissues. After 4 weeks of treatment, highly significant reductions were observed in number of CD4(+) T cell and B220(+) B cell subpopulations in the lamina propria of the colon and peripheral blood. KRP-203 obviously inhibited the production of interferon-gamma, IL-12, and tumor necrosis factor-alpha by the colonic lymphocytes, but had no influence on IL-4 production. KRP-203 significantly inhibits ongoing IL-10(-/-) colitis in part through decreasing the infiltration of lymphocytes at inflammatory sites and by blocking T-helper 1 cytokine production in the colonic mucosa. Therefore, the possibility arises that KRP-203 plays a potential role in control of chronic colitis.
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Affiliation(s)
- Jinghai Song
- Department of Complementary and Alternative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
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Mohan M, Aye PP, Borda JT, Alvarez X, Lackner AA. Gastrointestinal disease in simian immunodeficiency virus-infected rhesus macaques is characterized by proinflammatory dysregulation of the interleukin-6-Janus kinase/signal transducer and activator of transcription3 pathway. THE AMERICAN JOURNAL OF PATHOLOGY 2007; 171:1952-65. [PMID: 18055558 DOI: 10.2353/ajpath.2007.070017] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Gastrointestinal disease and inflammation are common sequelae of human and simian immunodeficiency virus (SIV) infection. Nevertheless, the molecular mechanisms that lead to gastrointestinal dysfunction remain unclear. We investigated regulation of the interleukin (IL)-6-JAK-STAT3 pathway in jejunum and colon, collected at necropsy, from 10 SIV-infected macaques with diarrhea (group 1), 10 non-SIV-infected macaques with diarrhea (group 2), and 7 control uninfected macaques (group 3). All group 1 and 2 macaques had chronic diarrhea, wasting, and colitis, but group 1 animals had more frequent and severe lesions in the jejunum. A significant increase in IL-6 and SOCS-3 gene expression along with constitutive STAT3 activation was observed in the colon of all group 1 and 2 macaques and in the jejunum of only group 1 macaques compared to controls. Further, in colon, histopathology severity scores correlated significantly with IL-6 (groups 1 and 2) and SOCS-3 (group 2) gene expression. In jejunum, a similar correlation was observed only in group 1 animals. Phosphorylated STAT3 (p-STAT3) was localized to lymphocytes (CD3+) and macrophages (CD68+), with fewer CD3+ lymphocytes expressing p-STAT3 in group 1 macaques. Despite high SOCS-3 expression, STAT3 remained constitutively active, providing a possible explanation for persistent intestinal inflammation and immune activation that may favor viral replication and disease pro-gression.
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Affiliation(s)
- Mahesh Mohan
- Division of Comparative Pathology, Tulane National Primate Research Center, 18703 Three Rivers Rd., Covington, LA 70433, USA
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Mudter J, Neurath MF. Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance. Inflamm Bowel Dis 2007; 13:1016-23. [PMID: 17476678 DOI: 10.1002/ibd.20148] [Citation(s) in RCA: 327] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) occurring in the gut of genetically susceptible individuals independent of a specific pathogen. The interaction between antigen-presenting cells and the local bacterial flora contributes to an uncontrolled activation of mucosal CD4+ T lymphocytes with the consecutive release of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6, IL-12, IL-23, IL-27, and also IL-17, which is attributed to a specific, differentiated CD4+ lineage called Th17 (TH-IL17, THi). Recent data suggest that IL-6 contributes to Th17 differentiation. However, to clarify the importance of Th17 cells in IBD further data are needed. So far, CD has been attributed to a Th1-mediated disease, whereas UC exhibits a modified Th2 cytokine response. In both diseases CD4+ T cells at the site of inflammation are critically dependent on antiapoptotic IL-6 signaling. Thereby, IL-6 induces the transcription factor STAT-3 via transsignaling (activation of a cell lacking membrane-bound IL-6 receptor via soluble IL-6 receptor). STAT-3 itself induces the antiapoptotic factors bcl-2 and bcl-xL, thus resulting in T-cell resistance against apoptosis. This vicious circle of T-cell accumulation, mediated by apoptosis resistance, finally leading to chronic inflammation, can be blocked by anti-IL-6 receptor antibodies. This review highlights the role of IL-6 in IBD immunopathogenesis and its clinical relevance in IBD therapy and diagnostics.
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Affiliation(s)
- Jonas Mudter
- 1st Medical Clinic, Johannes Gutenberg University of Mainz, Germany.
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O'Sullivan LA, Liongue C, Lewis RS, Stephenson SEM, Ward AC. Cytokine receptor signaling through the Jak–Stat–Socs pathway in disease. Mol Immunol 2007; 44:2497-506. [PMID: 17208301 DOI: 10.1016/j.molimm.2006.11.025] [Citation(s) in RCA: 241] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2006] [Revised: 11/21/2006] [Accepted: 11/22/2006] [Indexed: 12/31/2022]
Abstract
The complexity of multicellular organisms is dependent on systems enabling cells to respond to specific stimuli. Cytokines and their receptors are one such system, whose perturbation can lead to a variety of disease states. This review represents an overview of our current understanding of the cytokine receptors, Janus kinases (Jaks), Signal transducers and activators of transcription (Stats) and Suppressors of cytokine signaling (Socs), focussing on their contribution to diseases of an immune or hematologic nature.
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Affiliation(s)
- Lynda A O'Sullivan
- School of Life & Environmental Sciences, Deakin University, 221 Burwood Highway, Burwood, Victoria 3125, Australia
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Nishizawa M, Yamamoto H, Imagawa H, Barbier-Chassefière V, Petit E, Azuma I, Papy-Garcia D. Efficient syntheses of a series of trehalose dimycolate (TDM)/trehalose dicorynomycolate (TDCM) analogues and their interleukin-6 level enhancement activity in mice sera. J Org Chem 2007; 72:1627-33. [PMID: 17286434 DOI: 10.1021/jo062018j] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We found an IL-6 level-enhancing compound during our synthetic study of trehalose-6,6'-dimycolate (1, TDM, formerly called cord factor) analogues. TDM is a glycolipid distributed in the cell wall of Mycobacterium tuberculosis and shows significant antitumor activity based on an immunoadjuvant activity. However, due to its significant toxicity, TDM is not yet applicable for practical use. In 1993, Datta and Takayama reported the purification of trehalose-6,6'-dicorynomycolate (2c, TDCM) from Corynebacterium spp. We have previously reported the synthesis of four diastereomeric TDCMs and showed that the synthetic (2R,3R,2'R,3'R)-TDCM (2c, hereafter abbreviated RRRR-TDCM-C14) is identical to natural TDCM; we also demonstrated that 2c and SSSS-TDCM-C14 (3c) showed significant antitumor activity as well as inhibitory activity in experimental lung metastasis based on the immunoadjuvant activity. Furthermore, we found that the significant lethal toxicity in mice by TDM (1) was no longer observed with the shorter-chain analogues of TDCMs. Therefore, we have elucidated that the 2,3-antistereochemistry (RR or SS) of the fatty acid residue is promising for biological activities. The chain length of the fatty acid residue should also be important for the biological activity, and thus, we designed a general synthetic procedure for trehalose diesters with 2,3-antistereochemistry and a series of chain lengths by using Noyori's asymmetric reduction of beta,beta-ketoesters followed by antiselective alkylation according to Frater to give beta,beta-hydroxy alcohols as the key steps. Thus, we prepared trehalose diesters (TDCM) 2a-d, 3a-d, and 4a-d as well as monoesters (TMCM) 5a-d and 6a-d. Immunological activities of TDCMs and TMCMs were evaluated by determining IL-6 level enhancement in mouse serum, and we found that RRRR-TDCM-C14 (2c) and RRSS-TDCM-C14 (4c) showed significant IL-6 level enhancement activities.
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Affiliation(s)
- Mugio Nishizawa
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.
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Mitsuyama K, Sata M, Rose-John S. Interleukin-6 trans-signaling in inflammatory bowel disease. Cytokine Growth Factor Rev 2006; 17:451-61. [PMID: 17045835 DOI: 10.1016/j.cytogfr.2006.09.003] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
The pathogenesis of inflammatory bowel disease (IBD) is complex, involving a wide range of molecules including cytokines. Recent investigations support the important role of an interleukin-6 (IL-6) signaling pathway in the development of IBD. However, the molecular mechanisms of this pathway in the intestine remain incompletely understood. The circulating and intestinal levels of IL-6 as well as soluble IL-6 receptor (sIL-6R) are increased in patients with IBD. It is remarkable that the mucosal T cells of IBD patients are extremely resistant to apoptosis and that a large fraction of these cells express membrane-bound gp130 but not IL-6R. The accumulated evidence strongly supports the hypothesis that the development and perpetuation of IBD relies on the increased formation of IL-6/sIL-6R complexes interacting with membrane-bound gp130 on T cells via trans-signaling. These studies suggest that IL-6 trans-signaling may play a role in the development of IBD; they therefore imply the possibility of a selective therapeutic strategy to target this signaling.
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Affiliation(s)
- Keiichi Mitsuyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Asahi-machi 67, Kurume 830-0011, Japan.
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The regulatory role of Hyper-IL-6 in the differentiation of myeloid and erythroid progenitors derived from human cord blood. Cell Immunol 2006; 241:32-7. [PMID: 16934790 DOI: 10.1016/j.cellimm.2006.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2006] [Revised: 07/15/2006] [Accepted: 07/18/2006] [Indexed: 02/01/2023]
Abstract
This study was designed to investigate the regulatory role of soluble interleukin-6 receptor (sIL-6R) and interleukin-6 (IL-6) fusion protein (Hyper-IL-6) in the differentiation of human myeloid and erythroid progenitors by a serum-free liquid suspension culture system, using the human cord blood-derived CD34(+)CD38(-) cells as a target. We found that Hyper-IL-6 promoted the generation of CD15(+) granulocytic and CD14(+) monocytic cells and suppressed that of CD14(-)CD1a(+) dendritic cells from CD36(-)CD15(-)CD14(-)CD1a(-)IL-6R(+) myeloid progenitors. Conversely, CD34(+)CD38(-) cell-derived early erythroid progenitors were negative for IL-6R expression. Hyper-IL-6 potentiated the generation of CD36(+)glycophorinA(high) mature erythroid cells from the IL-6R(-) early erythroid progenitors. Our results indicate that Hyper-IL-6 augments the generation of CD15(+) granulocytic, CD14(+) monocytic and CD36(+)glycophorinA(high) cell and suppresses that of CD14(-)CD1a(+) dendritic cells.
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Sadeghi M, Daniel V, Naujokat C, Mehrabi A, Opelz G. Association of high pretransplant sIL-6R plasma levels with acute tubular necrosis in kidney graft recipients. Transplantation 2006; 81:1716-24. [PMID: 16794539 DOI: 10.1097/01.tp.0000226076.04938.98] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Delayed graft function is primarily caused by acute tubular necrosis (ATN). We studied in renal transplant recipients with posttransplant graft biopsy whether an up-regulated immune system in the recipient immediately before transplantation affects the risk of developing ATN and might be relevant for the pathogenesis of ATN. METHODS In a retrospective study, we analyzed pretransplant and early posttransplant soluble interleukin (sIL)-1RA, interleukin (IL)-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta2, interferon (IFN)-gamma, and neopterin plasma levels in patients with ATN (n=26). Matched patients with acute rejection (AR) (n=26) or normal posttransplant biopsy (n=26) served as controls. RESULTS Pretransplant sIL-6R was higher (P=0.0004) and pretransplant TGF-beta2 lower (P=0.002) in patients with ATN than in patients with normal biopsy. ROC curves showed that high pretransplant sIL-6R has a high sensitivity (77%) and high specificity (64%) for ATN (P=0.002). Posttransplant plasma sIL-6R continued to be higher in ATN patients than in patients with normal biopsy (P=0.001). Patients with acute rejection showed pre- and posttransplant sIL-6R and TGF-beta2 plasma levels similar to those of patients with normal biopsy (P=NS). CONCLUSION High pretransplant sIL-6R plasma levels are associated with an increased risk of ATN and might contribute to the development of ATN early posttransplant. Our data suggest that preactivation of the recipient's immune system increases the risk of ATN.
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Affiliation(s)
- Mahmoud Sadeghi
- Department of Transplantation-Immunology, University of Heidelberg, Heidelberg, Germany.
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Møller PL, Paerregaard A, Gad M, Kristensen NN, Claesson MH. Colitic scid mice fed Lactobacillus spp. show an ameliorated gut histopathology and an altered cytokine profile by local T cells. Inflamm Bowel Dis 2005; 11:814-9. [PMID: 16116315 DOI: 10.1097/01.mib.0000175906.77340.15] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Scid mice transplanted with CD4 T blast cells develop colitis. We investigated if the disease was influenced in colitic mice treated with antibiotic and fed Lactobacillus spp. METHODS Colitic scid mice were treated for 1 week with antibiotics (vancomycin/meropenem) followed or not followed by a 3-week administration of Lactobacillus reuteri DSM-12246 and Lactobacillus rhamnosus 19070-2 at 2x10 live bacteria/mouse/24 hours. After 12 weeks, the rectums were removed for histology, and CD4 T cells from the mesenteric lymph nodes (MLN) were polyclonally activated for cytokine measurements. RESULTS Irrespective of no treatment or treatments with antibiotics and probiotics, all mice transplanted with T cell blasts lost 10% of their body weight during the 12-week experimental period, whereas the nontransplanted mice had a 10% weight increase (P<0.001). All mice treated with antibiotics but not fed probiotics showed severe gut inflammation, whereas only 2 of the 7 mice fed probiotics showed signs of severe colitis (P<0.05). MLN-derived CD4 T cells from this latter group of mice showed lower levels of interleukin-4 secretion (P<0.05) and a tendency to higher interferon-gamma production than mice not fed probiotics. CONCLUSIONS Our data suggest that probiotics added to the drinking water may ameliorate local histopathological changes and influence local cytokine levels in colitic mice but not alter the colitis-associated weight loss.
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Affiliation(s)
- Peter Lange Møller
- Department of Dairy and Food Science, The Royal Veterinary and Agricultural University, and Department of Pediatrics, H:S Hvidovre Hospital, Copenhagen, Denmark
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Abad C, Juarranz Y, Martinez C, Arranz A, Rosignoli F, García-Gómez M, Leceta J, Gomariz RP. cDNA array analysis of cytokines, chemokines, and receptors involved in the development of TNBS-induced colitis: homeostatic role of VIP. Inflamm Bowel Dis 2005; 11:674-84. [PMID: 15973123 DOI: 10.1097/01.mib.0000171872.70738.58] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Crohn's disease (CD) is a chronic inflammatory pathology of the intestine, characterized by diarrhea and weight loss. A healing effect of vasoactive intestinal peptide (VIP) in the murine model of CD based on 2,4,6-trinitrobencene sulfonic acid (TNBS) administration has been previously shown. The aim of this work was to analyze the expression of several mediators related to the inflammatory cascade in colitic and VIP-treated animals. With this aim, mice received either only TNBS or TNBS and VIP treatment on alternate days. cDNA microarray analysis and real-time polymerase chain reaction were performed on total mRNA from colon to study the expression of a battery of proinflammatory molecules such as the enzyme COX-2, the chemokines CX3CL1, CXCL12, CXCL13, CXCL14, CCR5, and CXCR2, and the cytokines interleukin (IL)-1beta, IL-12, IL-18, IL-10, interferon-gamma, and IL-4. TNBS administration induced the expression of all the proinflammatory mediators studied, whereas VIP treatment reduced their levels, increasing the anti-inflammatory IL-10 and the TH2 cytokine IL-4, explaining its beneficial action through inhibition of the inflammatory/TH1 response. These data describe not only the relation of several proinflammatory mediators to the development of TNBS colitis, reporting their time-course, but also show the beneficial action of VIP in this model through complete blockage of the inflammatory cascade and recovery of the colon homeostasis, providing a potential new alternative for CD therapy.
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Affiliation(s)
- Catalina Abad
- Department of Cell Biology, Faculty of Biology, Complutense University, Madrid, Spain
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Day RM, Boccaccini AR. Effect of particulate bioactive glasses on human macrophages and monocytesin vitro. J Biomed Mater Res A 2005; 73:73-9. [PMID: 15714504 DOI: 10.1002/jbm.a.30262] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Bioactive glasses, originally developed to promote tissue adhesion, are finding an increasing array of biomedical applications. The aim of the current study was to assess the ability of silicate- and zinc phosphate-based bioactive glasses to modulate the secretion of cytokines from activated human macrophages and monocytes. Human macrophages and monocytes were isolated and cultured on surfaces coated with a range of quantities of the bioactive glasses. Nontoxic concentrations of the glasses were selected and assessed further for their ability to modulate the secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-10 and -6, in the presence or absence of the stimulant lipopolysaccharide. 45S5 glass produced a significant reduction to the amount of TNF-alpha (p<0.05) and IL-6 (p<0.01) secreted by stimulated cells compared with cells stimulated in the absence of bioactive glass. A significant reduction in IL-6 secretion was also observed with the other silicate- and zinc phosphate-based glasses tested. IL-10 secretion was increased (but not significantly) in presence of all glasses tested. TNF-alpha and IL-6 secretion from stimulated cells was lower in presence of the silicate glasses compared with the zinc phosphate glasses, indicating that this system of bioactive glass might be of clinical use in conditions associated with inflammation.
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Affiliation(s)
- Richard M Day
- Biomaterials & Tissue Engineering Group, Burdett Institute of Gastrointestinal Nursing, King's College London and St. Mark's Hospital, Watford Road, Harrow, HA1 3UJ, United Kingdom.
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Ramirez K, Huerta R, Oswald E, Garcia-Tovar C, Hernandez JM, Navarro-Garcia F. Role of EspA and intimin in expression of proinflammatory cytokines from enterocytes and lymphocytes by rabbit enteropathogenic Escherichia coli-infected rabbits. Infect Immun 2005; 73:103-13. [PMID: 15618145 PMCID: PMC538993 DOI: 10.1128/iai.73.1.103-113.2005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Enteropathogenic Escherichia coli (EPEC) produces attaching and effacing (A/E) lesions and watery diarrhea, both of which are intimin and EspA dependent. In this work, we explored the mucosal immune response by detecting cytokine induction in rabbits with diarrhea caused by rabbit EPEC (REPEC). Orally inoculated rabbits exhibited weight loss and mucosal inflammation, developed watery diarrhea, and died (day 7). At day 6 postinoculation, animals were analyzed for the induction of proinflammatory cytokines in enterocytes. The role of lymphocyte-dependent immunity was determined through the expression of proinflammatory cytokines by lymphocytes from Peyer's patches (PP) and the spleen. EspA and intimin mutants were used to explore the role of A/E lesions in the expression of these cytokines. REPEC-infected rabbit enterocytes showed increased interleukin 1beta (IL-1beta), IL-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) mRNA expression, but that of anti-inflammatory IL-10 was increased only slightly. In contrast, intimin mutant-infected rabbits were unable to produce this proinflammatory cytokine profile but did produce a remarkable increase in IL-10 expression. Bacteria lacking EspA increased the expression of IL-8 and TNF-alpha, but that of IL-10 was increased only slightly. PP lymphocytes also produced proinflammatory cytokines, which were dependent on EspA (except for TNF-alpha) and intimin, while IL-10 was induced by EspA and intimin mutants. In contrast, spleen lymphocytes (systemic compartment) were unable to produce IL-1beta and TNF-alpha. These data show the importance of the proinflammatory cytokines secreted by enterocytes and those expressed locally by PP lymphocytes, which can activate effector mechanisms at the epithelium. Furthermore, this cytokine profile, including IL-6 and IL-1beta, which may be involved in the diarrhea produced by EPEC, depends on intimin.
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Affiliation(s)
- Karina Ramirez
- Department of Cell Biology, CINVESTAV-IPN, Ap. Postal 14-740, 07000 México City, Mexico
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Mei FJ, Ishizu T, Murai H, Osoegawa M, Minohara M, Zhang KN, Kira JI. Th1 shift in CIDP versus Th2 shift in vasculitic neuropathy in CSF. J Neurol Sci 2004; 228:75-85. [PMID: 15607214 DOI: 10.1016/j.jns.2004.10.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2004] [Revised: 10/01/2004] [Accepted: 10/06/2004] [Indexed: 11/22/2022]
Abstract
To investigate the intra- and extracellular levels of various cytokines and chemokines in CSF in chronic inflammatory demyelinating polyneuropathy (CIDP) and vasculitic neuropathy (VN), 16 cytokines, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, IFN-gamma, TNF-alpha, G-CSF, MCP-1 and MIP-1beta, were measured in CSF supernatant by a multiplexed fluorescent bead-based immunoassay and intracellular production of IFN-gamma and IL-4 in CSF CD4+ T cells were simultaneously measured by flow cytometry in 14 patients with CIDP, 8 patients with VN and 25 patients with other noninflammatory neurologic diseases (OND). In the CSF supernatant, a significant increase of IL-17, IL-8 and IL-6, and a significant decrease of IL-4, IL-5 and IL-7 levels were detected in pretreated CIDP as compared with OND. A significant increase of IL-6, IL-8 and IL-10 levels was found in pretreated VN. Both IL-17 and IL-8 levels correlated strongly with CSF protein levels in CIDP, although the correlation of IL-6 levels was weak. In CSF CD4+ T cells, IFN-gamma+ IL-4- cell percentages were markedly elevated in CIDP compared with OND, but not in VN, resulting in a significant increase of intracellular IFN-gamma/IL-4 ratio in CIDP, even in the absence of CSF pleocytosis. The nonresponders to intravenous immunoglobulins (IVIGs) showed a significantly lower IFN-gamma- IL-4+ CD4+ T cell percentage, and tended to have a higher intracellular IFN-gamma/IL-4 ratio than the responders in CSF. Marked upregulation of Th1 cytokine, IL-17, and downregulation of Th2 cytokines, together with infiltration of IFN-gamma-producing CD4+ T cells are useful markers for CIDP, while several Th2 cytokines are upregulated in VN in CSF.
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Affiliation(s)
- Feng-Jun Mei
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Scheller J, Kovaleva M, Rabe B, Eichler J, Kallen KJ, Rose-John S. Development of a monoclonal antibody-based enzyme-linked immunoabsorbent assay for the binding of gp130 to the IL-6/IL-6R complex and its competitive inhibition. J Immunol Methods 2004; 291:93-100. [PMID: 15345308 DOI: 10.1016/j.jim.2004.05.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2003] [Revised: 04/16/2004] [Accepted: 05/05/2004] [Indexed: 01/04/2023]
Abstract
The proinflammatory cytokine IL-6 binds to the membrane bound or soluble IL-6 receptor (IL-6R) and activates an intracellular signaling cascade after complex formation with two gp130 molecules. These mediate general homeostasis and orchestrates the immune response during disease. Trans-signalling via the soluble IL-6R has importance for the development and maintenance of human diseases like Crohn's disease, peritonitis and rheumatoid arthritis. We have developed an enzyme-linked immunoabsorbent assay (ELISA) that detects the binding of gp130 to the IL-6/sIL-6R complex. Competitive binding of sgp130-Fc, viral IL-6, and the inhibitory drug Suramin to gp130 has been demonstrated. The assay can be used for high-throughput screening of peptide and chemical compound libraries for the identification of new agonists and antagonists of the binding between gp130 and IL-6/sIL-6R.
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Affiliation(s)
- Jürgen Scheller
- Institut für Biochemie, Christian-Albrechts Universität zu Kiel, Olshausenstr.40, D-24098 Kiel, Germany.
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Gallucci RM, Sloan DK, O'Dell SJ, Reinke LA. Differential expression of liver interleukin-6 receptor-alpha in female versus male ethanol-consuming rats. Alcohol Clin Exp Res 2004; 28:365-73. [PMID: 15084893 DOI: 10.1097/01.alc.0000118316.20560.0d] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND It is well known that women are more susceptible to alcoholic liver disease (ALD) than men, and inflammation is thought to play a major role in alcohol-induced liver injury. Increased circulating levels of the proinflammatory cytokine interleukin (IL)-6 are a marker for serious ALD in humans. However, IL-6 also has protective effects, such as induction of liver regeneration and inhibition of hepatocyte apoptosis. Although the roles of IL-6 in ALD have begun to be established, little is known about the expression of its receptor (IL-6Ralpha) during chronic alcohol administration. METHODS Male and female rats were intragastrically fed ethanol or control isocaloric liquid diet for 2 and 4 weeks. Liver samples were collected, and gene expression was assessed by reverse transcription-polymerase chain reaction and Western blot. RESULTS Herein, we show clear gender differences in alcohol-induced liver IL-6Ralpha expression. Analysis of rat liver samples showed that ethanol consumption significantly increased IL-6Ralpha messenger RNA and protein expression in females as compared with similarly treated males after 2 and 4 weeks. Increased STAT3 phosphorylation in the livers of ethanol-consuming females also indicated greater IL-6Ralpha activation in these animals. Conversely, ethanol-consuming males displayed increased IkappaB messenger RNA and protein expression, which may inhibit IL-6R expression, compared with females. CONCLUSIONS Given the association of inflammation with ethanol-induced liver damage, these data may offer insight into a possible mechanism by which females develop more severe ALD than males.
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Affiliation(s)
- Randle M Gallucci
- Department of Pharmaceutical Sciences Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190, USA.
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