Follistatin-like protein 1 promotes arthritis by up-regulating IFN-gamma.
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.
Clutter
Suzanne D
SD
Division of Rheumatology, Children's Hospital of Pittsburgh, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
Wilson
David C
DC
Marinov
Anthony D
AD
Hirsch
Raphael
R
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000601:surgery; D002460:Cell Line; D038702:Follistatin-Related Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D038702:Follistatin-Related Proteins; C448720:Fstl1 protein, mouse; D018836:Inflammation Mediators; D012333:RNA, Messenger; D007371:Interferon-gamma