| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
We examined the basic mechanism in the production of airway inflammation caused by influenza virus infection by examining the role of mitogen-activated protein (MAP) kinase in the production of cytokine and apoptosis. The results showed that 1) IV infection induced increases in p38 MAP kinase, Erk and JNK phosphorylation and activity, 2) SB 203580, PD 98059 and CEP-1347 attenuated IV-infection induced p38 MAP kinase activity, Erk activity and JNK activity, respectively, 3) SB 203580 and CEP-1347 attenuated RANTES production by 45.3 % and by 45.2 %, respectively, but a combination of these inhibitors additively attenuated by 69.1 %, in contrast, PD 98059 did not attenuate, 4) anti-IL-1 α mAb, anti-IL-1 β mAb, anti-TNF-α mAb, anti-IL-8 mAb, anti-IFN β mAb, anti-RANTES mAb and a combination of these mAbs did not affect IV infection-induced increases in p38 MAP kinase, Erk and JNK phosphorylation, indicating that each cytokine neutralized by corresponding ab was not involved in IV infectio
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ninduced phosphorylation of MAP kinases, 5) N-acetylcysteine (NAC) did not affect IV infectioninduced increases in MAP kinase phosphorylation, whereas NAC attenuated RANTES production by 18.2 %, indicating that reactive oxygen species (ROS) may act as a second messenger leading to RANTES production via p38 MAP kinase- and JNK-independent pathway. These results indicate, that p38 MAP kinase and JNK, at least in part, regulate RANTES production by BEC. The results from the next series experiment showed that 1) IV infection phosphorylated ASK1 and concomitantly phosphorylated JNK and p38 MAPK in human bronchial epithelial cells, 2) a time-course of ASK1 and MAPK phosphorylation revealed that ASK1 phosphorylation preceded MAPK phosphorylation, 3) the phosphorylation of JNK and p38 MAPK but not ERK in MEFs derived from ASK1 knockout mice (ASK1^<-/-> MEFs) was depressed compared to that in MEFs derived from wild type mice (ASK1^<+/+> MEFs), and 4) caspase-3 activation and cell death were depressed in ASK1^<-/-> MEFs compared to those in ASK1^<+/+> MEFs. These results indicate that apoptosis in IV-infected cells is mediated through ASK1-dependent cascades. Less
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