2001 Fiscal Year Final Research Report Summary
Beneficial or deleterious role of nitric oxide in the liver
| Project/Area Number |
11470491
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Kansai Medical University |
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Principal Investigator |
OKUMURA Tadayoshi Kansai University, Faculty of Engineering, Associate Professor, 医学部, 助教授 (80113140)
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| Co-Investigator(Kenkyū-buntansha) |
TAKETANI Shigeru Kyoto institute of Technology, Biotechnology, Associate Professor, 繊維学部, 助教授 (20121949)
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| Project Period (FY) |
1999 – 2001
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| Keywords | hepatocyte / inducible nitric oxide synthase / interleukin 1β / nuclear factor-kB / nitric oxide / liver injury |
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| Research Abstract |
Under the pathological conditions, in flammatory cytokines including nterleukin 1β (IL-1β) and tumore necrosis factor a induce an excess amount of nitric oxide (NO) production via the induction of inducible nitric oxide synthase (iNOS) in parenchym al liver cells (hepatocytes). NO has beep shown to exert either beneficial or deleterious actions in liver failure. However, regulation mechanism of iNOS induction through nuclear factor NF-_kB remains to be established.
In this study, we found details of regulation mechanism by endogenous or exogenous factors, where iNOS induction is inhibited or enhanced in primary cultures of rat hepatocytes. Nuclear factor C/EBPβ has been found to be associated with NF-KB presumably on the KB site of iNOS promoter, resulting in an acceleration of the transactivation activity. We also found that a vicinalthiol residue in NF-KB molecule (p50/p65), has a crucial role on its DNA binding. Experiment with ischemia/reperfusion revealed that hpypoxia inhibited iNOS induction, but had no influence on NF-KB activation (translocation to the nucleus and DNA binding at _kB site), suggesting that there exists a novel pathway (factor), hich is necessary to activate the transactivation of iNOS promoter in addition to NF-KB involving pathway. It seems that IL-lb has such signaling pathway in parallel with NF-KB activation at the downstream of its type I IL-1 receptor. Further investigation is needed to identify an additional signal on iNOS induction in hepatocytes. Such studies may provide the foundation for novel pharmacological approaches to reduce liver injury.
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