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Follistatin-Like Protein 1 Promotes Arthritis by Up-Regulating IFN-¹

Division of Rheumatology, Children’s Hospital of Pittsburgh, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213

Follistatin-like protein-1 (FSTL-1) is a poorly characterized protein that is up-regulated in the early stage of collagen-induced arthritis and that exacerbates arthritis when delivered by gene transfer. The current study was designed to determine the mechanism by which FSTL-1 promotes arthritis. FSTL-1 was injected into mouse paws, resulting in severe paw swelling associated with up-regulation of IFN- transcript and the IFN--induced chemokine, CXCL10. Mice depleted of T cells were protected. A central role for IFN- was confirmed by the finding that mice deficient in IFN- failed to exhibit paw swelling in response to injection of FSTL-1. Furthermore, IFN- secretion from mouse spleen cells exposed to a weak TCR signal was increased 5-fold in the presence of FSTL-1. FSTL-1 could be induced by innate immune signals, including TLR4 agonists and the arthritogenic cytokine, IL-1β, via an NFB pathway. Finally, FSTL-1 was found to be overexpressed in human arthritis and its neutralization inhibited murine collagen-induced arthritis and suppressed IFN- and CXCL10 production in arthritic joints. These findings demonstrate that FSTL-1 plays a critical role in arthritis by enhancing IFN- signaling pathways and suggest a mechanism by which FSTL-1 bridges innate and adaptive immune responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants AR052282 and AR48929, and the Children’s Hospital of Pittsburgh.

² Address correspondence and reprint requests to Dr. Raphael Hirsch, Division of Rheumatology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail address: raphael.hirsch{at}chp.edu

³ Abbreviations used in this paper: CIA, collagen-induced arthritis; FSTL-1, follistatin-like protein 1; RA, rheumatoid arthritis; CII, type II collagen.

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