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Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7971-6. Epub 2003 Jun 10.

A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses.

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  • 1Department of Neuropharmacology, The Harold L. Dorris Neurological Research Center, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. tbartfai@scripps.edu

Abstract

Toll-like receptors (TLRs) and the type I IL-1 receptor (IL-1RI) are key components of the innate immune system activated by microbial infections and inflammation. The signaling cascade from agonist-occupied TLRs and IL-1Rs involves recruitment of the small cytosolic adapter protein MyD88 that binds to IL-1RI via homotypic interactions mediated by Toll/IL-1R/resistance (TIR) domains. Dominant negative forms and null mutations of MyD88 have recently been shown to preclude bacterial product or IL-1-mediated activation of NF-kappaB pathways, demonstrating that MyD88 is an essential component of the Toll receptor signaling. Here, we report the synthesis and pharmacological effects of a low molecular weight MyD88 mimic, hydrocinnamoyl-l-valyl pyrrolidine (compound 4a), modeled on a tripeptide sequence of the BB-loop [(F/Y)-(V/L/I)-(P/G)] of the TIR domain. Results are presented showing that compound 4a interferes with the interactions between mouse MyD88 and IL-1RI at the TIR domains. Compound 4a inhibited IL-1beta-induced phosphorylation of the mitogen-activated protein kinase p38 in EL4 thymoma cells and in freshly isolated murine lymphocytes in a concentration-dependent manner. In vivo, compound 4a produced a significant attenuation of the IL-1beta-induced fever response (200 mg/kg, i.p.). Inhibition of the TIR domain-mediated MyD88/IL1-RI interaction by a low molecular weight, cell-penetrating TIR domain mimic suggests an intracellular site for antiinflammatory drug action.

PMID:
12799462
[PubMed - indexed for MEDLINE]
PMCID:
PMC164697
Free PMC Article

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