Guggulsterone suppresses the activation of transcription factor IRF3 induced by TLR3 or TLR4 agonists.
Toll-like receptors (TLRs) are vital in the induction of innate immune responses. The microbial components trigger the activation of the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-beta (TRIF)-dependent downstream TLR signaling pathways. Guggulsterone, which has been used for centuries to treat many chronic diseases, inhibits the MyD88-dependent pathway by inhibiting the activity of inhibitor-kappaB kinase. However, it is not known whether guggulsterone inhibits the TRIF-dependent pathway. Presently, we sought to identify the molecular targets of guggulsterone in this pathway. Guggulsterone inhibited nuclear factor-kappaB and IRF3 activation induced by lipopolysaccharide or poly[I:C] and activation of IRF3 induced by the overexpression of TRIF, TBK1 or constitutively active IRF3. Guggulsterone also suppressed the lipopolysaccharide-induced phosphorylation of IRF3. These results suggest that guggulsterone can modulate both MyD88- and TRIF-dependent signaling pathways of TLRs leading to decreased inflammatory gene expression.
Youn
Hyung-Sun
HS
Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan-Si, Chungnam 336-745, Republic of Korea.
Ahn
Sang-Il
SI
Lee
Boo-Yong
BY
D033942:Adaptor Proteins, Vesicular Transport / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D006801:Humans; D007202:Indicators and Reagents; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D011282:Pregnenediones / Q000494:pharmacology*; D051196:Toll-Like Receptor 3 / Q000819:agonists*; D051197:Toll-Like Receptor 4 / Q000819:agonists*; D014162:Transfection
D033942:Adaptor Proteins, Vesicular Transport; D007202:Indicators and Reagents; D050838:Interferon Regulatory Factor-3; D008156:Luciferases; D016328:NF-kappa B; D011282:Pregnenediones; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C023617:pregna-4,17-diene-3,16-dione