| Co-Investigator(Kenkyū-buntansha) |
IMOTO Toshiaki Tottori University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (10109639)
WATANABE Tathuo Tottori University, Faculty of Medicine, Professor, 医学部, 教授 (60182929)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2006: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2005: ¥500,000 (Direct Cost: ¥500,000)
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| Research Abstract |
We investigated whether proinflammatory transcription factors [nuclear factor-κB (NF-κB) and activator protein-1 (AP-1)] contribute to the angiotensin II (ANG II)-dependent production of cytokines within the brain. Interestingly, we found that a single i.c.v. injection of lipopolysaccharide (LPS) had no effect on NF-κB and AP-1 activities in the hypothalamus, hippocampus, and cerebellum (except for a decrease in hypothalamic AP-1 activity). Furthermore, both an angiotensin-converting-enzyme (ACE) inhibitor and an ANG type 1 (AT_1) receptor antagonist enhanced (rather than reduced) the NF-κB and AP-1 activities in the hippocampus and/or cerebellum of rats given LPS. These results seem not to support the idea that NF-κB and AP-1 play key roles in the ANG II-induced enhancement of the production of proinflammatory cytokines that is induced by LPS in the rat's brain. However, only a portion of whole brain cells is occupied by brain macrophage, microglial cells. Therefore, we then investiga
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ted whether ANG II and its receptors contributes to LPS-induced microglial activations through their effect on the activation of NF-κB and AP-1. To this end, examined were the effects of an ATI receptor antagonist, losartan, on the LPS-induced productions of interleukin-1 (IL-1) and nitric oxide (NO), morphological changes of the cells, as well as the activations of NF-κB and AP-1 in primary culture of microglial cells. Our RT-PCR study revealed that LPS-stimulated microglial cells had marked expression of mRNAs for ATI receptor. LPS-stimulated microglial cells showed increases in IL-1 and nitrite concentrations, as well as a morphological change. These effects were all inhibited by treatment with losartan. The activity of NF-κB and AP-1 was enhanced in LPS-stimulated microglial cells, that were significantly suppressed by losartan. Application of ANG II itself enhanced the LPS-induced increase in nitrite concentration. Collectively, these results suggest that the production of pyrogenic cytokines may be enhanced by ANG II and AT_1 receptor that stimulate microglial cells through the activation of transcription factors, NF-κB and AP-1 Less
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