A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses
- Tamas Bartfai*,†,‡,
- M. Margarita Behrens*,†,
- Svetlana Gaidarova*,†,
- Janell Pemberton*,†,
- Alexander Shivanyuk§,¶, and
- Julius Rebek, Jr‡,§,¶
- Departments of *Neuropharmacology and §Chemistry, †The Harold L. Dorris Neurological Research Center, and ¶The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037
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Contributed by Julius Rebek, Jr., May 7, 2003
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-κB 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-1β-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-1β-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.
Footnotes
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↵ ‡ To whom correspondence should be addressed. E-mail: tbartfai{at}scripps.edu or jrebek{at}scripps.edu.
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Abbreviations: TLR, Toll-like receptor; IL-1RI, type I IL-1 receptor; IL-1RAcP, IL-1R accessory protein; TIR, Toll/IL-1R/resistance; LPS, lipopolysaccharide; DCM, dichloromethane; MAP, mitogen-activated protein; ERK, extracellular signal-regulated kinase; JNK, c-Jun aminoterminal kinase.
- Copyright © 2003, The National Academy of Sciences
