Studies on the role of the JAK-STAT pathway in the regulation of growth and the function of insulin-secreting cells.

最近的研究已经确定JAK-STAT途径作为各种细胞因子和生长因子的主要信号事件。本研究的目的是研究JAK-STAT通路的作用，在调节生长和胰岛素分泌细胞的功能，使用大鼠胰岛素瘤细胞系INS-1.1。(1)生长激素（GH）和催乳素（PRL），这两者都刺激胰岛素分泌细胞的生长和胰岛素生物合成，激活JAK 2酪氨酸激酶，然后磷酸化和STAT 5的DNA结合。(2)与以前在其他细胞类型中的报道相反，GH未能激活INS-I细胞中的丝裂原活化蛋白（MAP）激酶。这可能是由于该细胞系中表皮生长因子（EGF）受体的表达有限，而该受体被GH磷酸化. (1)IFN-γ主要通过抑制INS-Ⅰ细胞线粒体代谢来抑制营养诱导的胰岛素分泌。此外，IFN-γ与肿瘤坏死因子（TNF）-α的组合在INS-I细胞中引起细胞毒性作用。这与诱导型一氧化氮（NO）合酶（iNOS）的表达平行观察，从而产生NO，这可能导致细胞毒性。(2)IFN-γ促进STAT 1的酪氨酸磷酸化和DNA结合，而TNF-α激活NE-κ B，发现其被IFN-γ进一步激活。IEN-γ对STAT 1的激活可能直接或间接地通过激活IRF-1参与了NO的表达，另外，两种细胞因子对NE-κ B的协同激活可能是诱导iNOS的重要事件。而IFN-γ对STAT 1的作用可能导致胰岛素分泌细胞生长和功能的抑制。

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.