Tumor necrosis factor-alpha signals to the IFN-gamma receptor complex to increase Stat1 alpha activation

We describe a novel mechanism of signaling interaction through which tumor necrosis factor-alpha (TNF-alpha) treatment augments interferon-gamma (IFN- gamma)-induced Stat1 alpha DNA-binding complexes and transcriptional activa tion of a Stat-binding element. In TNF-alpha-treated cells, IFN-gamma-induc ed phosphorylation of Jak2 kinase is increased, Jak2 kinase activity is enh anced, and genetic studies indicate that TNF-alpha requires Jak2 kinase act ivity to enhance Stat1 alpha tyrosine phosphorylation, Increased Jak2 and S tat1 alpha phosphorylation are observed within minutes of coexposure to TNF -alpha/IFN-gamma, suggesting a direct signaling interaction. IFN-gamma rece ptor chain 1 (IFNGR-1) tyrosine phosphorylation is markedly enhanced in cel ls treated with TNF-alpha/IFN-gamma without alteration in receptor levels. Thus, there exists a direct signaling interaction between TNF-alpha and IFN -gamma, independent of cooperating enhancer elements, that may be relevant for cytokine action during immune-mediated host defense and inflammatory pr ocesses.