| Budget Amount *help |
¥10,100,000 (Direct Cost: ¥10,100,000)
Fiscal Year 1999: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 1998: ¥5,500,000 (Direct Cost: ¥5,500,000)
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| Research Abstract |
The role of Interferon Regulatory Factors, IRF-1, and IRF-2, and IFN-related cytokine, TNF in acute hepatitis model was studied. We found that IRF-1 deficient mice were more liable to die than the control, when mice treated with LPS following p.acnes priming. As the level of TNF and Fas ligand expression was not changed in the IRF-1 deficient mice, involvement of a pathway other than Fas-Fas ligand system is suggested. On the other hand, TNF receptor deficient mice were resistant to the stimulation, indicating the importance of TNF. Interestingly, CC chemokine Macrophage inflammatory protein-3alpha (MIP-3alpha), was induced to express in the liver after the stimulation, and that the induction was definitely dependent on the NF-kappaB activation induced by TNF. Since MIP3 alpha initiates the inflammatory reactions by chemoattracting T cells, MIP3 alpha must be critical molecule in the hepatic injury model. IRF-1 has ben know to be induced by TNF or IFN. We found that the promoter region of the IRF-1 contains a novel TNF-responsive element, which binds NF-kappaB. This element also attributable to the responsiveness to IFN.
We also demonstrate that mice IRF-2 deficient mice exhibited abnormal maturation of pancreatic acinar cells, and developed lethal pancreatitis after poly(I) : poly(C) injection. However, the liver seemed almost free of damage. These results indicate the novel role of IRF-2 in development and pathogenesis of pancreas, and for the first time that viral mimicry is a causative agent to produce acute pancreatits.
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