TBK1-targeted suppression of TRIF-dependent signaling pathway of Toll-like receptors by 6-shogaol, an active component of ginger.
Toll-like receptors (TLRs) are primary sensors that detect a wide variety of microbial components involving induction of innate immune responses. After recognition of microbial components, TLRs trigger the activation of myeloid differential factor 88 (MyD88) and Toll-interleukin-1 (IL-1) receptor domain-containing adapter inducing interferon-beta (TRIF)-dependent downstream signaling pathways. 6-Shoagol, an active ingredient of ginger, inhibits the MyD88-dependent signaling pathway by inhibiting inhibitor-kappaB kinase activity. Inhibitor-kappaB kinase is a key kinase in nuclear factor kappaB (NF-kappaB) activation. However, it is not known whether 6-shogaol inhibits the TRIF-dependent signaling pathway. Our goal was to identify the molecular target of 6-shogaol in the TRIF-dependent pathway of TLRs. 6-Shogaol inhibited the activation of interferon-regulatory factor 3 (IRF3) induced by lipopolysaccharide (LPS) and by polyriboinosinic polyribocytidylic acid (poly[I:C]), overexpression of TRIF, TANK-binding kinase1 (TBK1), and IRF3. Furthermore, 6-shogaol inhibited TBK1 activity in vitro. Together, these results suggest that 6-shogaol inhibits the TRIF-dependent signaling pathway of TLRs by targeting TBK1, and, they imply that 6-shogaol can modulate TLR-derived immune/inflammatory target gene expression induced by microbial infection.
Park
Se-Jeong
SJ
Department of Medical Science, College of Medical Sciences, Soonchunhyang University, Asan-Si, Chungnam, Korea.
Lee
Mi-Young
MY
Son
Bu-Soon
BS
Youn
Hyung-Sun
HS
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D002396:Catechols / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D020939:Zingiber officinale / Q000737:chemistry*; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D002396:Catechols; D016328:NF-kappa B; D051193:Toll-Like Receptors; C040115:shogaol; D017346:Protein Serine-Threonine Kinases