title: Parthenolide inhibits TRIF-dependent signaling pathway of Toll-like receptors in RAW264.7 macrophages.
abstract: Toll-like receptors (TLRs) play an important role in induction of innate immune responses for host defense against invading microbial pathogens. Microbial component engagement of TLRs can trigger the activation of myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent downstream signaling pathways. Parthenolide, an active ingredient of feverfew (Tanacetum parthenium), has been used for centuries to treat many chronic diseases. Parthenolide inhibits the MyD88-dependent pathway by inhibiting the activity of inhibitor-κB kinase. However, it is not known whether parthenolide inhibits the TRIF-dependent pathway. To evaluate the therapeutic potential of parthenolide, its effect on signal transduction via the TRIF-dependent pathway of TLRs induced by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly [I:C]) was examined. Parthenolide inhibited nuclear factor-κB and interferon regulatory factor 3 activation induced by LPS or poly[I:C], and the LPS-induced phosphorylation of interferon regulatory factor 3 as well as interferon-inducible genes such as interferon inducible protein-10. These results suggest that parthenolide can modulate TRIF-dependent signaling pathways of TLRs, and may be the basis of effective therapeutics for chronic inflammatory diseases.
authors.affiliation: Department of Medical Science, College of Medical Sciences, Soonchunhyang University, Asan, 336-745, Korea.
authors.forename: Se-Jeong
authors.initials: SJ
authors.lastname: Park
authors.forename: Hwa-Jeong
authors.initials: HJ
authors.lastname: Shin
authors.forename: Hyung-Sun
authors.initials: HS
authors.lastname: Youn
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments; D011070:Poly I-C / Q000494:pharmacology; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D054357:Chemokine CXCL10; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D008156:Luciferases; D016328:NF-kappa B; D010446:Peptide Fragments; D011070:Poly I-C; D012717:Sesquiterpenes; D051193:Toll-Like Receptors; C494233:Irf3 protein, mouse; C476286:Ticam1 protein, mouse; C072032:thrombin receptor peptide (42-55); C002669:parthenolide