Journal
JOURNAL OF IMMUNOLOGY
Volume 182, Issue 1, Pages 234-239Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.182.1.234
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Funding
- National Institutes of Health [AR052282, AR48929]
- Children's Hospital of Pittsburgh
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI073556] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [P01AR048929, T32AR052282, R01AR056959] Funding Source: NIH RePORTER
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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-1 beta, via an NF kappa B 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. The Journal of Immunology, 2009, 182: 234-239.
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