Ras/Erk pathway positively regulates Jak1/STAT6 activity and IL-4 gene expression in Jurkat T cells

T helper cells can be largely divided into two functional subsets, Th1 and Th2, which are characterized by the cytokines they produce. The mechanism of Th1 versus Th2 cytokine production is thought to involve interaction of TCR-induced signal and cytokine-induced signal, mainly activating the Ras/MAPK and the Jak/STAT pathway, respectively. In order to gain insight into the signal transduction network for Th1 and Th2 differentiation, we have analyzed the functional cross-talk between the Jak/STAT and the Ras/MAPK pathway. In cytokine-producing Jurkat T cells, we have found that IL-4 induces activation of Erk and Akt, and the IL-4-induced STAT6 activity is suppressed by inhibitors of Erk and PI3K. The transfection of daRas into theses cells resulted in the up-regulation of specific activity of Jak1/STAT6 with a concomitant increase in Erk and Akt activity, while siRNA-mediated knock-out of Ras resulted in the inhibition of Jak1/STAT6. Furthermore, the IL-4 mRNA expression and IL-4 promoter activity were enhanced by daRas but not by dnRas. The Ras-induced increase of both STAT6 activity and IL-4 mRNA level was effectively blocked by a Mek/Erk inhibitor. suggesting that Ras/Erk pathway positively regulates STAT6 activity and IL-4 transcription. Together, the results indicate that there is a functional cross-talk between Ras/Erk and IL-4/Jak1/STAT6, which contributes to the regulation of IL-4 transcription in T cells. (c) 2007 Elsevier Ltd. All rights reserved.