|Budget Amount *help
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1997: ¥1,100,000 (Direct Cost: ¥1,100,000)
Recent investigations have established the JAK-STAT pathway as major signalling events for various cytokines and growth factors. The aim of this study was to investigate the role of the JAK-STAT pathway in the regulation of growth and the function of insulin-secreting cells using a rat insulinoma cell line INS-1.
1. (1) Growth hormone (GH) and prolactin (PRL), both of which stimulate growth and insulin biosynthesis of insulin-secreting cells, activated JAK2 tyrosine kinase followed by phosphorylation and DNA-binding of STAT5. (2) In contrast to previous reports in other cell types, GH failed to activate mitogen-activated protein (MAP) kinase in INS-I cells. This could be explained by limited expression of epidermal growth factor (EGF) receptor, which was found to be phosphorylated by GH, in this cell line.
2. (1) Interferon (IFN)-gamma inhibited nutrient-induced insulin secretion mainly through the inhibition of mitochondrial metabolism in INS-I cells. Moreover, IFN-gamma in combination with tumor necrosis factor (TNF)-alpha elicited cytotoxic effects in INS-I cells. This was observed in parallel with expression of the inducible isoform of nitric oxide (NO) synthase (iNOS), thereby producing NO, which may cause cytotoxicity. (2) IFN-gamma promoted tyrosine phosphorylation and DNA-binding of STAT 1, whereas TNF-alpha activated NE-kappaB, which was found to be further activated by IFN-gamma. The activation of STAT1 by IEN-gamma may be involved, directly or indirectly via the activation of IRF-1, in the expression of NO.In addition, the synergistic activation of NE-kappaB by the two cytokines might be an essential event for the iNOS induction.
Taken together, it is suggested that the activation of JAK2 and STAT5 by GH or PRL is implicated in the stimulation, whereas that of STAT1 by IFN-gamma may lead to the inhibition, of growth and the function of insulin-secreting cells.