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Inflammation can be mediated by invading microbial pathogens. Toll-like receptors (TLRs) recognize invading microbial pathogens, inducing innate immune responses. Broadly, the activation of TLRs induces two major downstream signaling pathways, myeloid differential factor 88 (MyD88)- and Toll/interleukin 1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent pathways, which lead to the activation of nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3). To evaluate the therapeutic potential of the ethanol extracts of flowers of Eupatorium japonicum Thunb (EJE), its effect on signal transduction via the TLR signaling pathways induced by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly[I:C]) was examined. EJE suppressed the activation of NF-κB and IRF3 induced by LPS or poly[I:C]. EJE also inhibited LPS- or poly[I:C]-induced IRF3 phosphorylation as well as interferon-inducible genes, such as interferon inducible protein-10. These results suggest that EJE can modulate TLR signaling pathways, realizing effective therapeutic options for chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) recognize specific patterns derived from invading microbial pathogens. TLR activation by microbial components triggers the activation of myeloid differential factor 88 (MyD88)- and tollinterleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent downstream signaling pathways, leading to the activation of nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3). Triptolide (TP), an active ingredient of Tripterygium wilfordii Hook. F, has been reported to have positive effects on autoimmune and inflammatory diseases. To evaluate the therapeutic potential of TP, 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. TP inhibited NF-κB and IRF3 activation and IRF3 phosphorylation induced by LPS or poly[I:C]. TP also inhibited interferon-inducible genes such as, interferon inducible protein-10. These results suggest that TP can modulate TRIF-dependent signaling pathways of TLRs, and will become promising drug candidates in TLRs-based therapy in the future. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) play an important role in induction of innate immune responses. The stimulation of TLRs by microbial components triggers two branches of downstream signaling pathways: myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent signaling pathways. Auranofin, a sulfur-containing gold compound (Au[I]), has been widely used for the treatment of rheumatoid arthritis. Since dysregulation of TLRs can lead to severe systemic inflammatory and joint destructive process in rheumatoid arthritis, auranofin-mediated modulation of TLR activation may have therapeutic potential against such diseases. Previously, we demonstrated that auranofin suppressed TLR4 signaling pathway by inhibiting TLR4 dimerization induced by LPS. Here, we examined the effect of auranofin on signal transduction via the TRIF-dependent pathway induced by a TLR3 agonist. Auranofin inhibited nuclear factor-κB and interferon (IFN) regulatory factor 3 (IRF3) activation induced by polyinosinic-polycytidylic acid (poly[I:C]). Auranofin inhibited poly[I:C]-induced phosphorylation of IRF3 as well as IFN-inducible genes such as IFN inducible protein-10. Furthermore, auranofin inhibited TBK1 kinase activity in vitro. All the results suggest that auranofin suppress TLR signaling at multiple steps. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) play an important role in initiating innate immune responses. The stimulation of TLRs by microbial components triggers the activation of two downstream signaling pathways: myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent signaling pathways. Wood vinegar (WV), a byproduct from charcoal production, has been evaluated for its various biological activities including anti-oxidant, anti-bacterial, and anti-inflammatory activities. To evaluate the therapeutic potential of WV, we examined its effect on signal transduction via the TRIF-dependent pathway of TLRs induced by TLR3 and TLR4 agonists. Oak wood vinegar (OWV) inhibited nuclear factor-κB and interferon regulatory factor 3 activation induced by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly [I: C]). OWV also inhibited LPS- or poly[I:C]-induced interferon inducible protein-10 (IP-10). These results suggest that OWV can modulate TRIF-dependent signaling pathway of TLRs for anti-viral, anti-bacterial, and anti-inflammatory activities. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) play an important role in host defense by sensing invading microbial pathogens and initiating innate immune responses. The stimulation of TLRs by microbial components triggers the activation of myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent downstream signaling pathways. Isoliquiritigen in (ILG), an active ingredient of Licorice, has been used for centuries to treat many chronic diseases. ILG inhibits the MyD88-dependent pathway by inhibiting the activity of inhibitor-κB kinase. However, it is not known whether ILG inhibits the TRIF-dependent pathway. To evaluate the therapeutic potential of ILG, we examined its effect on signal transduction via the TRIF-dependent pathway of TLRs induced by several agonists. ILG inhibited nuclear factor-κB and interferon regulatory factor 3 activation induced by lipopolysaccharide or polyinosinic-polycytidylic acid. ILG inhibited the lipopolysaccharide-induced phosphorylation of interferon regulatory factor 3 as well as interferon-inducible genes such as interferon inducible protein-10, and regulated activation of normal T-cell expressed and secreted (RANTES). These results suggest that ILG can modulate TRIF-dependent signaling pathways of TLRs, leading to decreased inflammatory gene expression. [ABSTRACT FROM AUTHOR]