Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adaptor Proteins, Signal Transducing*
-
Animals
-
Arthritis, Experimental / genetics
-
Arthritis, Experimental / metabolism
-
Carrier Proteins / metabolism
-
Fas Ligand Protein
-
Fas-Associated Death Domain Protein
-
Humans
-
Inflammation / metabolism*
-
Interleukin-6 / metabolism
-
Lipopolysaccharides / metabolism
-
Macrophages / metabolism*
-
Membrane Glycoproteins / genetics
-
Membrane Glycoproteins / metabolism*
-
Mice
-
Receptors, Cell Surface / metabolism*
-
Receptors, Interleukin-1 / metabolism*
-
Toll-Like Receptor 4
-
Toll-Like Receptors
-
fas Receptor / genetics
-
fas Receptor / metabolism
Substances
-
Adaptor Proteins, Signal Transducing
-
Carrier Proteins
-
FADD protein, human
-
FASLG protein, human
-
Fadd protein, mouse
-
Fas Ligand Protein
-
Fas-Associated Death Domain Protein
-
Fasl protein, mouse
-
Interleukin-6
-
Lipopolysaccharides
-
Membrane Glycoproteins
-
Receptors, Cell Surface
-
Receptors, Interleukin-1
-
TLR4 protein, human
-
Toll-Like Receptor 4
-
Toll-Like Receptors
-
fas Receptor