期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：13
页码：7971-7976
DOI：10.1073/pnas.0932746100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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-{kappa}B 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-1{beta}-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-1{beta}-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.
