Pharmacological role and clinical applications of interleukin-6 in rheumatoid disease

Abstract: Interleukin (IL)-6 is a pleiotropic cytokine that promotes polyclonal activation of association of the transducing glycoprotein 130 with the membrane-anchored receptor (R) α, IL-6 can generate functionally distinct signals. Given these particular molecular aspects, numerous activities ascribed to this cytokine are, in fact, due to the insertion into soluble IL-6Rα. The system is instrumental in rheumatoid arthritis (RA), Sjogren’s syndrome and systemic lupus erythema-tosus (SLE). In this respect, it is interesting that the expression of the recombination-activating gene is sustained by IL-6 in B lymphocytes, and repressed by anti-IL-6R antibody (Ab) in RA and SLE. Agents that inhibit IL-6 signaling have now entered clinical trials. As expected, clinical benefits are reported in the treatment of autoimmunedisorders with anti-IL-6R Ab, but other perspectives remain open in the forthcoming biotherapies of immune-mediated disorders. Keywords: interleukin-6, B lymphocyte, rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, biotherapy

[1]  P. Youinou,et al.  The weight of interleukin-6 in B cell-related autoimmune disorders. , 2009, Journal of autoimmunity.

[2]  R. Gay,et al.  Expression, regulation, and signaling of the pattern-recognition receptor nucleotide-binding oligomerization domain 2 in rheumatoid arthritis synovial fibroblasts. , 2009, Arthritis and rheumatism.

[3]  Hiu Kiu,et al.  SOCS regulation of the JAK/STAT signalling pathway. , 2008, Seminars in cell & developmental biology.

[4]  H. Knüpfer,et al.  sIL‐6R: more than an agonist? , 2008, Immunology and cell biology.

[5]  J. Pers,et al.  Polarization of B effector cells in Sjögren's syndrome. , 2007, Autoimmunity reviews.

[6]  D. M. van der Heijde,et al.  Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab , 2007, Annals of the rheumatic diseases.

[7]  P. Youinou B cell conducts the lymphocyte orchestra. , 2007, Journal of autoimmunity.

[8]  T. Kishimoto,et al.  Interleukin 6: from bench to bedside , 2006, Nature Clinical Practice Rheumatology.

[9]  S. Romagnani Regulation of the T cell response , 2006, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[10]  I. McInnes,et al.  New cytokine targets in inflammatory rheumatic diseases. , 2006, Best practice & research. Clinical rheumatology.

[11]  J. Scheller,et al.  Interleukin-6 and its receptor: from bench to bedside , 2006, Medical Microbiology and Immunology.

[12]  J. Scheller,et al.  Interleukin‐6 Trans‐Signalling in Chronic Inflammation and Cancer , 2006, Scandinavian journal of immunology.

[13]  L. Staudt,et al.  Clinical Trials and Observations , 2007 .

[14]  Simon A. Jones,et al.  Directing Transition from Innate to Acquired Immunity: Defining a Role for IL-61 , 2005, The Journal of Immunology.

[15]  J. Scheller,et al.  IL-6 transsignaling: the in vivo consequences. , 2005, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[16]  P. Woo,et al.  Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. , 2005, Arthritis and rheumatism.

[17]  N. Miyasaka,et al.  Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. , 2004, Arthritis and rheumatism.

[18]  R. Jonsson,et al.  Circulating Cytokines in Primary Sjögren's Syndrome Determined by a Multiplex Cytokine Array System , 2004, Scandinavian journal of immunology.

[19]  T. Hibi,et al.  A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. , 2004, Gastroenterology.

[20]  P. Heinrich,et al.  Principles of interleukin (IL)-6-type cytokine signalling and its regulation. , 2003, The Biochemical journal.

[21]  Y. Takahama,et al.  Effect of CpG methylation on RAG1/RAG2 reactivity: implications of direct and indirect mechanisms for controlling V(D)J cleavage , 2003, EMBO reports.

[22]  I. Todd,et al.  Assessment of Be1 and Be2 cells in systemic lupus erythematosus indicates elevated interleukin-10 producing CD5+ B cells , 2003, Lupus.

[23]  K. Yoshizaki,et al.  Influences of anti-mouse interleukin-6 receptor antibody on immune responses in mice. , 2002, Immunology letters.

[24]  R. Price,et al.  Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. , 2002, Arthritis and rheumatism.

[25]  T. Hirano,et al.  IL-6 in autoimmune disease and chronic inflammatory proliferative disease. , 2002, Cytokine & growth factor reviews.

[26]  M. Szyf,et al.  Interleukin-6 Regulation of the Human DNA Methyltransferase (HDNMT) Gene in Human Erythroleukemia Cells* , 2001, The Journal of Biological Chemistry.

[27]  R. Jonsson,et al.  Increased Frequency of Cells Secreting Interleukin‐6 and Interleukin‐10 in Peripheral Blood of Patients with Primary Sjögren's Syndrome , 1999, Scandinavian journal of immunology.

[28]  T. Kishimoto,et al.  Anticytokine therapy in autoimmune diseases. , 1999, Internal medicine.

[29]  V. Poli,et al.  Interleukin 6 Dependence of Anti-DNA Antibody Production: Evidence for Two Pathways of Autoantibody Formation in Pristane-induced Lupus , 1998, The Journal of experimental medicine.

[30]  Y. Saeki,et al.  Interleukin 6 plays a key role in the development of antigen-induced arthritis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[31]  L. D. Ward,et al.  High affinity interleukin-6 receptor is a hexameric complex consisting of two molecules each of interleukin-6, interleukin-6 receptor, and gp-130. , 1994, The Journal of biological chemistry.

[32]  J. Abrams,et al.  Cytokine mRNA expression in salivary gland biopsies of Sjögren's syndrome. , 1994, Journal of immunology.

[33]  H. Nagafuchi,et al.  Constitutive expression of IL-6 receptors and their role in the excessive B cell function in patients with systemic lupus erythematosus. , 1993, Journal of immunology.

[34]  D. Wendling,et al.  Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. , 1993, The Journal of rheumatology.

[35]  C. Gordon,et al.  Urinary IL‐6: a marker for mesangial proliferative glomerulonephritis? , 1991, Clinical and experimental immunology.

[36]  T. Hirano,et al.  Molecular cloning and expression of an IL-6 signal transducer, gp130 , 1990, Cell.

[37]  S. Akira,et al.  Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF) , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  M. Jourdan,et al.  Constitutive production of interleukin-6 and immunologic features in cardiac myxomas. , 1990, Arthritis and rheumatism.

[39]  T. Taniguchi,et al.  Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. , 1988, Science.

[40]  J. Smolen,et al.  Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlle , 2010, Arthritis and rheumatism.

[41]  A. Puisieux,et al.  Interleukin 17 acts in synergy with B cell–activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus , 2009, Nature Immunology.

[42]  F. Sallusto,et al.  Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. , 2007, Nature immunology.

[43]  D. Kimpel,et al.  Double-Blind Randomized Controlled Clinical Trial of the Interleukin-6 Receptor Antagonist, Tocilizumab, in European Patients With Rheumatoid Arthritis Who Had an Incomplete Response to Methotrexate , 2007 .

[44]  D. Littman,et al.  The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. , 2006, Cell.

[45]  K. Yoshioka,et al.  Cellular localization of inflammatory cytokines in human glomerulonephritis , 2004, Virchows Archiv.

[46]  T. Hirano,et al.  IL-6 signal transduction and its physiological roles: the signal orchestration model. , 2003, Reviews of physiology, biochemistry and pharmacology.

[47]  M. Neurath,et al.  Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. , 2001, European journal of biochemistry.

[48]  P. Lipsky,et al.  Regulation of human B lymphocyte activation, proliferation, and differentiation. , 1987, Advances in immunology.