The p38 MAPK Pathway Is Involved in the IL-2 Induction of TNF-β Gene via the EBS Element

As an important cytokine of the immune system, interleukin-2 (IL-2) can induce the expression of various genes, one of which is the tumor necrosis factor-β (TNF-β). However, the induction mechanism of TNF-β remains to be fully explored. We have previously shown JAK-STAT pathway mediates TNF-β gene induction upon IL-2 stimulation through an upstream −200GAS element. In this study, we further demonstrated that there is another essential −130EBS element in TNF-β gene promoter region. Using IL-2-dependent cell line BAF/BO3β, we found that this −130EBS element can form a specific complex with nuclear protein, which contained a novel ETS transcription factor. Furthermore, using kinase inhibitors, we revealed that p38 MAP kinase is involved in the formation of −130EBS–protein complex and the subsequent transcriptional activation of TNF-β gene in response to IL-2 stimulation. Taken together, our results suggested that the complicated IL-2 induction of TNF-β gene expression requires not only the activation of JAK-STAT pathway on the −200GAS element, but also the cooperation of another signal pathway on the −130EBS element.