RESUMEN
Toll-like receptors (TLRs) are a group of pattern-recognition receptors (PRRs) that are at the core of innate and adaptive immune responses. TLRs activation triggers the activation of two downstream signaling pathways, the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-ß (TRIF)-dependent pathways. To evaluate the therapeutic potential of DHL, a natural sesquiterpene lactone derived from Inulahelenium L. and Saussurea lappa, we examined its effect on signal transduction via the TLR signaling pathways. DHL inhibited the activation of nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3), the representative transcription factors involved in the inflammatory response, induced by TLR agonists, as well as the expression of cyclooxygenase-2 and interferon inducible protein-10. DHL also inhibited the activation of NF-κB and IRF3 induced by the overexpression of downstream signaling components of the TLRs signaling pathways. All results suggest that DHL might become a new therapeutic drug for a variety of inflammatory diseases.
Asunto(s)
Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Lactonas/farmacología , Sesquiterpenos/farmacología , Transducción de Señal/efectos de los fármacos , Receptores Toll-Like/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Antiinflamatorios/uso terapéutico , Células HEK293 , Humanos , Inflamación/inmunología , Factor 3 Regulador del Interferón/metabolismo , Inula/química , Lactonas/uso terapéutico , Ratones , Factor 88 de Diferenciación Mieloide/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Células RAW 264.7 , Saussurea/química , Sesquiterpenos/uso terapéutico , Transducción de Señal/inmunologíaRESUMEN
Toll-like receptors (TLRs) play a crucial role in the induction of innate immune response against bacterial and viral infections. TLRs induce downstream signaling via MyD88- and TRIF-dependent pathways. Cardamonin is a naturally occurring chalcone from Alpinia species exhibiting anti-inflammatory effects. However, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the role of cardamonin in TLR signaling pathways. Cardamonin inhibited NF-κB activation as well as COX-2 expression induced by TLR agonists. Cardamonin inhibited the activation of IRF3 and the expression of interferon-inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. Cardamonin also inhibited ligand-independent NF-κB activation overexpressed by MyD88, IKKß, or p65 and IRF3 activation overexpressed by TRIF, TBK1, or IRF3. However, cardamonin had no effect on TBK1 kinase activity in vitro. These results suggest that cardamonin modulates both the MyD88- and TRIF-dependent pathways of TLRs and represents a potentially new anti-inflammatory candidate.