Negative regulation of toll-like receptor-mediated signaling by Tollip - PubMed (original) (raw)

. 2002 Mar 1;277(9):7059-65.

doi: 10.1074/jbc.M109537200. Epub 2001 Dec 18.

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Negative regulation of toll-like receptor-mediated signaling by Tollip

Guolong Zhang et al. J Biol Chem. 2002.

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Abstract

Toll-like receptor (TLR)-mediated recognition of pathogens represents one of the most important mechanisms of innate immunity and disease resistance. The adaptor protein Tollip was identified initially as an intermediate in interleukin (IL)-1 signaling. Here we report that Tollip also associates directly with TLR2 and TLR4 and plays an inhibitory role in TLR-mediated cell activation. Inhibition by Tollip is mediated through its ability to potently suppress the activity of IL-1 receptor-associated kinase (IRAK) after TLR activation. In addition, we show for the first time that Tollip is a bona fide substrate for IRAK and is phosphorylated by IRAK upon stimulation with lipopolysaccharide or IL-1. Negative regulation of TLR signaling by Tollip may therefore serve to limit the production of proinflammatory mediators during inflammation and infection.

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