Parthenolide inhibits TRIF-dependent signaling pathway of toll-like receptors in RAW264.7 macrophages |
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Authors: | Se-Jeong Park Hwa-Jeong Shin Hyung-Sun Youn |
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Affiliation: | (1) Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8007, 63110 St. Louis, MO, USA; |
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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. |
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Keywords: | lipopolysaccharide parthenolide polyinosinic-polycytidylic acid Toll-like receptors TRIF |
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