Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130.
Studies in IL-6-deficient (IL-6(-/-)) mice highlight that IL-6 contributes to arthritis progression. However, the molecular mechanism controlling its activity in vivo remains unclear. Using an experimental arthritis model in IL-6(-/-) mice, we have established a critical role for the soluble IL-6R in joint inflammation. Although intra-articular administration of IL-6 itself was insufficient to reconstitute arthritis within these mice, a soluble IL-6R-IL-6 fusion protein (HYPER-IL-6) restored disease activity. Histopathological assessment of joint sections demonstrated that HYPER-IL-6 increased arthritis severity and controlled intrasynovial mononuclear leukocyte recruitment through the CC-chemokine CCL2. Activation of synovial fibroblasts by soluble IL-6R and IL-6 emphasized that these cells may represent the source of CCL2 in vivo. Specific blockade of soluble IL-6R signaling in wild-type mice using soluble gp130 ameliorated disease. Consequently, soluble IL-6R-mediated signaling represents a promising therapeutic target for the treatment of rheumatoid arthritis.
Nowell
Mari A
MA
Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, United Kingdom.
Richards
Peter J
PJ
Horiuchi
Sankichi
S
Yamamoto
Naoki
N
Rose-John
Stefan
S
Topley
Nicholas
N
Williams
Anwen S
AS
Jones
Simon A
SA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015703:Antigens, CD / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000096:biosynthesis; D050822:Cytokine Receptor gp130; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000032:analysis / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology; D019947:Receptors, Interleukin-6 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D012995:Solubility; D013582:Synovial Fluid / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D018932:Chemokine CCL2; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D050822:Cytokine Receptor gp130