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

Nat Immunol. 2004 Apr;5(4):380-7. doi: 10.1038/ni1054. Epub 2004 Mar 7.

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