Interleukin-6 subfamily cytokines and rheumatoid arthritis: role of antagonists.
Many cytokines have been implicated in the inflammatory pathways that characterize rheumatoid arthritis (RA) and related inflammatory diseases of the joints. These include members of the interleukin-6 (IL-6) family of cytokines, several of which have been detected in excess in the synovial fluid from RA patients. What makes the IL-6 group of cytokines a family is their common use of the glycoprotein 130 (gp130) receptor subunit, to which they bind with different affinities. Several strategies have been developed to block the pro-inflammatory activities of IL-6 subfamily cytokines. These include the application of monoclonal antibodies, the creation of mutant form(s) of the cytokine with enhanced binding affinity to gp130 receptor and the generation of antagonists by selective mutagenesis of the specific cytokine/gp130 receptor-binding site(s). The rationale for the use of anti-cytokine therapy in inflammatory joint diseases is based on evidence from studies in vitro and in vivo, which implicate major cytokines such as interleukin-1 (IL-1), tumour necrosis factor (TNF)-alpha and IL-6 in RA pathogenesis. In particular, IL-6 subfamily antagonists have a wide range of potential therapeutic and research applications. This review focuses on the role of some of the IL-6 subfamily cytokines in the pathogenesis of the inflammatory diseases of the joints (IJDs), such as RA. In addition, an overview of the recently developed antagonists will be discussed.
Jazayeri
Jalal A
JA
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Melbourne, Australia. jalal.jazayeri@pharm.monash.edu.au
Carroll
Graeme J
GJ
Vernallis
Ann B
AB
D000818:Animals; D000911:Antibodies, Monoclonal; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D015195:Drug Design; D006023:Glycoproteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D015850:Interleukin-6 / Q000031:analogs & derivatives / Q000276:immunology*; D016297:Mutagenesis, Site-Directed; D011993:Recombinant Fusion Proteins; D013582:Synovial Fluid; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D006023:Glycoproteins; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D000093242:Interleukin-6 Inhibitors; C480482:glycoprotein 130, human