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.