title: A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses.
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.
authors.affiliation: Department 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
authors.forename: Tamas
authors.initials: T
authors.lastname: Bartfai
authors.forename: M Margarita
authors.initials: MM
authors.lastname: Behrens
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gaidarova
authors.forename: Janell
authors.initials: J
authors.lastname: Pemberton
authors.forename: Alexander
authors.initials: A
authors.lastname: Shivanyuk
authors.forename: Julius
authors.initials: J
authors.lastname: Rebek
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000737:chemistry*; D015153:Blotting, Western; D003720:Densitometry; D004797:Enzyme-Linked Immunosorbent Assay; D005799:Genes, Dominant; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D009154:Mutation; D053594:Myeloid Differentiation Factor 88; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000737:chemistry*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014633:Valine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D007375:Interleukin-1; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011759:Pyrrolidines; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; C475931:hydrocinnamoyl-1-valyl pyrrolidine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014633:Valine; C032519:pyrrolidine