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Sci. STKE, 6 April 2004
Vol. 2004, Issue 227, p. tw123
[DOI: 10.1126/stke.2272004tw123]

EDITORS' CHOICE

IMMUNOLOGY Adaptor Wars

Fas, a receptor associated with apoptosis triggering, is reported to be an enhancer of signaling through members of the Toll-interleukin 1 (TIR) family (Ma et al.), and ST2, which is a member of the TIR family, is reported to be an inhibitor of TIR signaling (Brint et al.). Cytokine production by joint macrophages contributes to chronic inflammation associated with rheumatoid arthritis. Ma et al. showed that collagen-induced arthritis symptoms were reduced in mice deficient for Fas (DBA/1lpr/lpr mice) compared with heterozygous littermates. Despite having increased levels of interleukin 1β (IL-1β) and its receptor IL-1R in the paws of the Fas-deficient animals, there was less IL-6, an inflammatory mediator produced in response to IL-1β. Disruption of Fas activation in isolated macrophages resulted in decreased production of IL-6 and activation of nuclear factor {kappa}B (NF-{kappa}B) in response to IL-1R activation by IL-1β or TLR4 (Toll-like receptor 4) in response to lipopolysaccharide (LPS). Crosstalk between Fas signaling and TIR signaling occurred at the level of the adaptor proteins. MyD88, which mediates IL-R1 and TLR4 signaling, and FADD (Fas-associated protein with death domain), which mediates Fas signaling, interact and the outcome is that in the absence of Fas signaling, FADD sequesters MyD88, making it less available for TIR signaling. In the presence of Fas activation, FADD is recruited to the Fas signaling complex and MyD88 is free to mediate TIR signaling. Brint et al. reported that ST2 also acts to sequester the TIR adaptors MyD88 and Mal. In macrophages from ST2-deficient mice, there was enhanced cytokine production in response to stimuli that activate TLR4, TLR9, TLR2, or IL-R1. The TIR domain of ST2 binds the adaptors MyD88 and Mal, which results in decreased availability of these adaptors for mediating TLR signaling. ST2 is not abundant in macrophages from unchallenged mice, and ST2-deficient mice showed the same mortality to LPS as wild-type mice. However, cytokine production and mortality were decreased in ST2-deficient macrophages and mice, respectively, compared with wild type if there was a sublethal LPS exposure before the LPS challenge. Thus, ST2 is stimulated in response to TLR signaling and can then attenuate subsequent responses, which contributes to endotoxin tolerance.

Y. Ma, H. Liu, H. Tu-Rapp, H.-J. Thiesen, S. M. Ibrahim, S. M. Cole, R. M. Pope, Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation. Nat. Immunol. 5, 380-387 (2004). [Online Journal]

E. K. Brint, D. Xu, H. Liu, A. Dunne, A. N. J. McKenzie, L. A. J. O'Neill, F. Y. Liew, ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat. Immunol. 5, 373-379 (2004). [Online Journal]

Citation: Adaptor Wars. Sci. STKE 2004, tw123 (2004).


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