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Toll-like receptor 4 (TLR4) recognizes LPS and triggers the activation of the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter, inducing interferon-β (TRIF)-dependent major downstream signaling pathways. Previously, we presented biochemical evidence that 1-[4-Fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine (FPP), which was synthesized in our laboratory, inhibits NF-κB activation induced by LPS. Here, we investigated whether FPP modulates the TLR4 downstream signaling pathways and what anti-inflammatory target in TLR4 signaling is regulated by FPP. FPP inhibited LPS-induced NF-κB activation by targeting TLR4 dimerization. These results suggest that FPP can modulate the TLR4 signaling pathway at the receptor level to decrease inflammatory gene expression. [ABSTRACT FROM PUBLISHER]

Abstract: Toll-like receptors (TLRs) play important inductive roles in innate immune responses for host defense against invading microbial pathogens. Activation of TLR4 by lipopolysaccharide (LPS) induces dimerization of TLR4 and, subsequently, activation of downstream signaling pathways including nuclear factor-kappa B and interferon regulatory factor 3. TLR4 dimerization may be an early regulatory event in activating signaling pathways induced by LPS. Here, biochemical evidence is reported that isoliquiritigenin, one of the major ingredients derived from licorice root, inhibits LPS-induced TLR4 dimerization resulting in inhibition of nuclear factor-kappa B and interferon regulatory factor 3 activation, and cyclooxygenase-2 and inducible nitric oxide synthase expression. These results suggest that isoliquiritigenin modulates TLR-mediated signaling pathways at the receptor level. Furthermore, these results suggest that TLRs themselves may be important targets for the prevention of chronic inflammatory diseases. [Copyright &y& Elsevier]

Abstract: Toll-like receptors (TLRs) play an important role in the recognition of microbial pathogens and induce innate immune responses. The recognition of microbial components by TLRs 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. Previously, we synthesized (E)-1-(2-(2-nitrovinyl)phenyl)pyrrolidine (NVPP), which contains a nitrovinyl-phenyl and pyrrolidine. To evaluate the therapeutic potential of NVPP, 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. NVPP inhibited LPS or poly[I:C]-induced activation of nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3), and the phosphorylation of IRF3, as well as inhibiting the activation of interferon-inducible genes such as interferon inducible protein-10 (IP-10). These results suggest that NVPP can modulate TRIF-dependent signaling pathways of TLRs, potentially resulting in effective therapeutics for chronic inflammatory diseases. [Copyright &y& Elsevier]

Abstract: Toll-like receptors (TLR) play a significant role in the induction of innate immune responses that are essential for host defense against invading microbial pathogens. In general, TLRs have two major downstream signaling pathways: myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent pathways. Allyl isothiocyanate (AITC) found in cruciferous vegetables has an effect on treatment of many chronic diseases. However, the exact molecular targets of AITC are still unidentified. Here, it was investigated whether AITC can modulate TLR signaling pathways and what is the molecular target of AITC in TLRs signaling pathways. AITC suppressed the activation of nuclear factor-κB by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly[I:C]), but not by macrophage-activating lipopeptide of 2kDa (MALP-2) or cytosine-phosphate-guanine dinucleotide (CpG DNA). AITC also suppressed the activation of interferon regulatory factor 3 (IRF3) and the expression of interferon inducible protein-10 (IP-10) induced by LPS or poly[I:C]. These results suggest that AITC can modulate TRIF-dependent signaling pathways of TLRs leading to decreased inflammatory gene expression. [Copyright &y& Elsevier]