Follistatin-like protein 1 promotes arthritis by up-regulating IFN-gamma

• Published in: The Journal of immunology (1950) 2009-01, Vol.182 (1), p.234-239
• Main Authors: Clutter, Suzanne D, Wilson, David C, Marinov, Anthony D, Hirsch, Raphael
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - immunology; Arthritis, Experimental - metabolism; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - surgery; Cell Line; Follistatin-Related Proteins - biosynthesis; Follistatin-Related Proteins - genetics; Follistatin-Related Proteins - physiology; Humans; Inflammation Mediators - metabolism; Inflammation Mediators - physiology; Interferon-gamma - biosynthesis; Interferon-gamma - deficiency; Interferon-gamma - genetics; Interferon-gamma - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, Knockout; Mice, Transgenic; RNA, Messenger - biosynthesis; Signal Transduction - genetics; Signal Transduction - immunology; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.182.1.234

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-gamma transcript and the IFN-gamma-induced chemokine, CXCL10. Mice depleted of T cells were protected. A central role for IFN-gamma was confirmed by the finding that mice deficient in IFN-gamma failed to exhibit paw swelling in response to injection of FSTL-1. Furthermore, IFN-gamma 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-1beta, via an NFkappaB pathway. Finally, FSTL-1 was found to be overexpressed in human arthritis and its neutralization inhibited murine collagen-induced arthritis and suppressed IFN-gamma and CXCL10 production in arthritic joints. These findings demonstrate that FSTL-1 plays a critical role in arthritis by enhancing IFN-gamma signaling pathways and suggest a mechanism by which FSTL-1 bridges innate and adaptive immune responses.