| Summary: | 碩士 === 長庚大學 === 天然藥物研究所 === 93 === Enterovirus 71 (EV71) is a widespread virus that causes severe and fatal diseases in patients, including circulation failure. The blood vessel will be damaged first , and produced necrosis and inflammation, this phenomenon is called vasculitis. Vasculitis is an inflammatory disorder mediated by vascular cell adhesion molecule-1 (VCAM-1) or nitric oxide. In previous study, the value of plasma levels of VCAM-1 and NO in the pathogenesis and prognosis was investigated in body with virus infections of varying severity. But the mechanisms underlying EV71-initiated intracellular signaling pathways to influence host cell functions remain unknown. In this study, we have identified EV71-indued PDGFR, Akt, ERK, p38, NF-B activation and iNOS, VCAM-1 expression in a time- and viral dose-dependent manner. Treatment of RV-SMCs with EV71 stimulated phosphorylation of PDGFR, Akt, ERK, and p38which was attenuated by AG1296, LY294002, Wortmannin, U0126, and SB202190, respectively. The PDGFR inhibitor (AG1296), PI3-K inhibitor (LY294002, Wortmannin), and ERK inhibitor (U0126) inhibited EV-71-induced iNOS expression. And the PDGFR inhibitor (AG1296), PI3-K inhibitor (LY294002, Wortmannin), p38 inhibitor (SB202190), and JNK inhibitor (SP600125) inhibited EV-71-induced VCAM-1 expression. Furthermore, iNOS and VCAM-1 expression induced by EV71 was significantly attenuated by a selective NF-B inhibitor (Helenalin). Consistently, EV71-stimulated translocation of NF-B into the nucleus and degradation of IB-α was blocked by Helenalin, AG1296, SB202190, SP600125, LY294002, and Wortmannin. These findings suggest that EV71 interacting through adhesion receptors initiates PDGFR-, PI3-K/Akt, p38-, and NF-B-dependent signaling pathways that mediate VCAM-1 expression in RV-SMCs, but not via p42/p44 MAPK. In addition, EV71 interacting through adhesion receptors initiates PDGFR-, PI3-K/Akt, p42/p44 MAPK-, and NF-κB-dependent signaling pathways that mediate iNOS expression in RV-SMCs.
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