Abstract
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.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Antigens, CD / pharmacology*
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Arthritis, Experimental / genetics
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Arthritis, Experimental / immunology*
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Arthritis, Experimental / pathology
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Arthritis, Experimental / prevention & control*
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Arthritis, Rheumatoid / immunology
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Arthritis, Rheumatoid / metabolism
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Cell Movement / genetics
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Cell Movement / immunology
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Chemokine CCL2 / biosynthesis
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Cytokine Receptor gp130
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Fibroblasts / immunology
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Fibroblasts / metabolism
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Humans
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Interleukin-6 / administration & dosage
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Interleukin-6 / deficiency
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Interleukin-6 / genetics
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Interleukin-6 / metabolism*
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / pathology
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Male
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Membrane Glycoproteins / pharmacology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Protein Isoforms / analysis
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / pharmacology
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Protein Isoforms / physiology
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Receptors, Interleukin-6 / administration & dosage
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Receptors, Interleukin-6 / antagonists & inhibitors*
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Receptors, Interleukin-6 / genetics
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Receptors, Interleukin-6 / physiology*
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / therapeutic use
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Severity of Illness Index
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Signal Transduction / genetics
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Signal Transduction / immunology
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Solubility
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Synovial Fluid / chemistry
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Synovial Fluid / immunology
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Synovial Fluid / metabolism
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antigens, CD
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Chemokine CCL2
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IL6ST protein, human
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Il6st protein, mouse
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Interleukin-6
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Membrane Glycoproteins
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Protein Isoforms
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Receptors, Interleukin-6
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Recombinant Fusion Proteins
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Cytokine Receptor gp130