Study on possible role of cytokines in response to oxidative stress by using cytokine knock out mice

2000 Fiscal Year Final Research Report Summary

• Project/Area Number: 11672183
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Showa university
• Principal Investigator: OGURO Takiko Showa Univ., Sch.Pharmaceut.Sci., lecturer, 薬学部, 講師 (10185572)
• Co-Investigator(Kenkyū-buntansha): YOSHIDA Takemi Showa Univ., Sch.Pharmaceut.Sci., Professor, 薬学部, 教授 (20138415)
• Project Period (FY): 1999 – 2000
• Keywords: TNFα / LPS / cytokine / MAPK / heme oxygenase / BCG / CYP / metallothionein

Research Abstract

Cytokines constitute very sophisticated network, by which they play important roles in the activation of responsible cells and production of cytokines themselves. Therefore, it is difficult to determine function of an individual cytokine. In this study, we examined the effect of each cytokine on their target cells, especially the expression of HO-1 in the liver, in IL-1 α/β (IL-1), TNFα and IL-6 knockout mice. We found that in addition to IL-1, TNFα also played an important role in HO-1 gene expression by LPS.Based on these findings, we also examined major signal transduction from LPS in cytokine knockout mice. LPS has been shown to lead HO-1 gene expression via activation of AP-1. Therefore, we determined the effect of LPS on signal transduction from MAPK cascade leading to HO-1 gene expression in TNFα KO mice, which produced little response to the agent. We found the marked decrease in the activation of p38 and JNK, but no differences in the of phosphorylation of ERK, between wild and TNFα KO mice. The results suggest that TNFα plays actively in the LPS-mediated induction of HO-1 gene expression, and its signal is conducted via p38 and/or JNK.Additionally, we clarified the important role of cytokine KO mice in the study on BCG-mediated regulation of cytochrome P450 and metallothionein.