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

Nature Immunology volume 5, pages 380–387 (2004)Cite this article

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-1β (IL-1β) 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-κB activation and cytokine expression induced by IL-1β 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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Figure 1: DBA/1lpr/lpr mice are resistant to collagen-induced arthritis.
Figure 2: Interruption of Fas ligation suppresses IL-1β- and LPS-induced cytokine expression.
Figure 3: LPS induces less IL-6 in lpr and gld macrophages.
Figure 4: Interruption of Fas ligation suppresses LPS- and IL-1β-induced NF-κB activation.
Figure 5: FADD suppresses MyD88-induced IL-6 and NF-κB promoter activation.
Figure 6: FADD modulates LPS- and IL-1β-induced cytokine expression.
Figure 7: Fas ligation reduces the association of FADD with MyD88.

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Acknowledgements

We thank M.E. Peter and V.M. Dixit for providing the FADD and dominant negative FADD plasmids; J. Karras for providing the antisense FADD deoxyoligonucleotides; and R. Medzhitov for providing the MyD88 plasmid. We also thank H. Perlman, P.H. Stern, N.A. Clipstone and A. Lin for critical review of the manuscript; M.E. Peter for advice on the immunoprecipitation experiments; C.J. Zander for technical assistance; and H.-J. Kreutzer for help evaluating joint histopathology. Supported by the National Institutes of Health (R01-AR049217) and The Veterans Administration Research Service (Merit Review), the National and Greater Chicagoland Chapters of the Arthritis Foundation and Deutsche Forschungsgemeinschaft (IB 24/3-1 to S.M.I.).

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Authors and Affiliations

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

    Yingyu Ma, Hongtao Liu, Shawn M Cole & Richard M Pope

  2. Integrated Graduate Program in the Life Sciences, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Ward 12-361, Chicago, 60611, Illinois, USA

    Yingyu Ma

  3. Department of Immunology, University of Rostock, Schillingallee 70, Rostock, 18055, Germany

    Hoang Tu-Rapp, Hans-Juergen Thiesen & Saleh M Ibrahim

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Ma, Y., Liu, H., Tu-Rapp, H. et al. Fas ligation on macrophages enhances IL-1R1–Toll-like receptor 4 signaling and promotes chronic inflammation. Nat Immunol 5, 380–387 (2004). https://doi.org/10.1038/ni1054

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