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Updated: Aug 11, 2026

Using RNA-interference to Investigate the Innate Immune Response in Mouse Macrophages
Published on: November 3, 2014
Negative regulation of toll-like receptor-mediated signaling by Tollip
1Section of Immunobiology, Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520, USA.
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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