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ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance

Abstract

The Toll–interleukin 1 receptor (TIR) superfamily, defined by the presence of an intracellular TIR domain, initiates innate immunity through activation of the transcription factor NF-κB, leading to the production of proinflammatory cytokines. ST2 is a member of the TIR family that does not activate NF-κB and has been suggested as an important effector molecule of T helper type 2 (TH2) responses. We show here that the membrane-bound form of ST2 negatively regulated type I interleukin 1 receptor (IL-1RI) and Toll-like receptor 4 (TLR4) but not TLR3 signaling by sequestrating the adaptors MyD88 and Mal. In contrast to wild-type mice, ST2-deficient mice failed to develop endotoxin tolerance. Thus, these results provide a molecular explanation for the function of ST2 in TH2 responses, as inhibition of TLRs promotes a TH2 response, and also identify ST2 as a key regulator of endotoxin tolerance.

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Figure 1: Macrophages from ST2-deficient mice produce more proinflammatory cytokines than do cells from wild-type mice.
Figure 2: ST2 inhibits activation of NF-κB induced by IL-1 and LPS but not poly(I:C).
Figure 3: ST2 inhibits and interacts with MyD88 and Mal but not Trif or IRAK.
Figure 4: ST2 is required for endotoxin tolerance.

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Acknowledgements

Supported by Science Foundation Ireland, The Wellcome Trust, The Medical Research Council, UK, and the European Commission.

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Correspondence to Luke A J O'Neill or Foo Y Liew.

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Brint, E., Xu, D., Liu, H. et al. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol 5, 373–379 (2004). https://doi.org/10.1038/ni1050

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