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      Role of Interleukin-6 Family Cytokines in Organ Fibrosis

      review-article
      a , a , b , a ,
      Kidney Diseases
      S. Karger AG
      Interleukin-6 family cytokines, Organ fibrosis

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          Abstract

          Background

          Organ fibrosis remains an important cause of high incidence rate and mortality worldwide. The prominent role of interleukin-6 (IL-6) family members represented by IL-6 in inflammation has been extensively studied, and drugs targeting IL-6 have been used clinically. Because of the close relationship between inflammation and fibrosis, researches on the role of IL-6 family members in organ fibrosis are also gradually emerging.

          Summary

          In this review, we systematically reviewed the role of IL-6 family members in fibrosis and their possible mechanisms. We listed the role of IL-6 family members in organ fibrosis and drew two diagrams to illustrate the downstream signal transductions of IL-6 family members. We also summarized the effect of some IL-6 family members' antagonists in a table.

          Key Messages

          Fibrosis contributes to organ structure damage, organ dysfunction, and eventually organ failure. Although IL-6 family cytokines have similar downstream signal pathways, different members play various roles in an organ-specific manner which might be partly due to their different target cell populations. The pathogenic role of individual member in various diseases needs to be deciphered carefully.

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          Most cited references92

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          IL-6 in inflammation, immunity, and disease.

          Interleukin 6 (IL-6), promptly and transiently produced in response to infections and tissue injuries, contributes to host defense through the stimulation of acute phase responses, hematopoiesis, and immune reactions. Although its expression is strictly controlled by transcriptional and posttranscriptional mechanisms, dysregulated continual synthesis of IL-6 plays a pathological effect on chronic inflammation and autoimmunity. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody was developed. Various clinical trials have since shown the exceptional efficacy of tocilizumab, which resulted in its approval for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Moreover, tocilizumab is expected to be effective for other intractable immune-mediated diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated to facilitate the development of more specific therapeutic approaches and analysis of the pathogenesis of specific diseases.
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            Fibrosis: from mechanisms to medicines

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              The pro- and anti-inflammatory properties of the cytokine interleukin-6.

              Interleukin-6 is a cytokine not only involved in inflammation and infection responses but also in the regulation of metabolic, regenerative, and neural processes. In classic signaling, interleukin-6 stimulates target cells via a membrane bound interleukin-6 receptor, which upon ligand binding associates with the signaling receptor protein gp130. Gp130 dimerizes, leading to the activation of Janus kinases and subsequent phosphorylation of tyrosine residues within the cytoplasmic portion of gp130. This leads to the engagement of phosphatase Src homology domains containing tyrosin phosphatase-2 (SHP-2) and activation of the ras/raf/Mitogen-activated protein (MAP) kinase (MAPK) pathway. In addition, signal transducer and activator of transcription factors are recruited, which are phosphorylated, and consequently dimerize whereupon they translocate into the nucleus and activate target genes. Interestingly, only few cells express membrane bound interleukin-6 receptor whereas all cells display gp130 on the cell surface. While cells, which only express gp130, are not responsive to interleukin-6 alone, they can respond to a complex of interleukin-6 bound to a naturally occurring soluble form of the interleukin-6 receptor. Therefore, the generation of soluble form of the interleukin-6 receptor dramatically enlarges the spectrum of interleukin-6 target cells. This process has been named trans-signaling. Here, we review the involvement of both signaling modes in the biology of interleukin-6. It turns out that regenerative or anti-inflammatory activities of interleukin-6 are mediated by classic signaling whereas pro-inflammatory responses of interleukin-6 are rather mediated by trans-signaling. This is important since therapeutic blockade of interleukin-6 by the neutralizing anti-interleukin-6 receptor monoclonal antibody tocilizumab has recently been approved for the treatment of inflammatory diseases. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. 2011 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Kidney Dis (Basel)
                Kidney Dis (Basel)
                KDD
                KDD
                Kidney Diseases
                S. Karger AG (Basel, Switzerland )
                2296-9381
                2296-9357
                22 March 2023
                August 2023
                : 9
                : 4
                : 239-253
                Affiliations
                [a ]Department of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
                [b ]Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
                Author notes
                Correspondence to: Jing Nie, niejing@ 123456smu.edu.cn
                Article
                530288
                10.1159/000530288
                10601952
                3f99e412-7e6a-47d4-8842-611ba8c7eb2e
                © 2023 The Author(s). Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC) ( http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.

                History
                : 29 November 2022
                : 2 March 2023
                : 2023
                Page count
                Figures: 2, Tables: 2, References: 92, Pages: 15
                Funding
                This work was supported by grants from Nature and Science Foundation of China (81730019, 82090020), Nature and Science Foundation of Guangdong Province (2019B1515120075), and Outstanding Scholar Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR110102004) to Dr. Jing Nie.
                Categories
                Review Article

                interleukin-6 family cytokines,organ fibrosis
                interleukin-6 family cytokines, organ fibrosis

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