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Nat Immunol. 2004 Apr;5(4):380-7. Epub 2004 Mar 7.

Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation.

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Northwestern University Feinberg School of Medicine and Veteran's Administration Medical Center, Chicago, Lakeside Division, Department of Medicine, Division of Rheumatology, 300 E. Superior Avenue, Tarry 3-713, Chicago, Illinois 60611, USA.


The nonapoptotic functions of Fas ligation are incompletely characterized. In contrast to expectations, we show here that Fas-deficient mice developed less-severe collagen-induced arthritis than did control mice. Despite having milder arthritis, Fas-deficient mice had more of the critical pro-inflammatory mediator interleukin-1 beta (IL-1 beta) in their joints, suggesting inefficient activation through IL-1 receptor 1 (IL-1R1) when Fas signaling is deficient. In primary human macrophages and macrophages from Fas- or Fas ligand (FasL)-deficient mice, interruption of Fas-FasL signaling suppressed nuclear factor-kappa B activation and cytokine expression induced by IL-1 beta and lipopolysaccharide. This cross-talk was mediated by the Fas-associated death domain through interaction with myeloid differentiation factor 88. These observations document a unique mechanism whereby Fas-FasL interactions enhance activation through the IL-1R1 or Toll-like receptor 4 pathway, which may contribute to the pathogenesis of chronic arthritis.

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