Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130

Nowell, Mari Ann, Richards, Peter James, Horiuchi, Sankichi, Yamamoto, Naoki, Rose-John, Stefan, Topley, Nicholas, Williams, Anwen Sian ORCID: https://orcid.org/0000-0001-6118-020X and Jones, Simon Arnett ORCID: https://orcid.org/0000-0001-7297-9711 2003. Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130. The Journal of Immunology 171 (6) , pp. 3202-3209.

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine Systems Immunity Research Institute (SIURI)
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Last Modified:	06 Nov 2024 22:35
URI:	https://orca.cardiff.ac.uk/id/eprint/286

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