Tumor necrosis factor-alpha signals to the IFN-gamma receptor complex to increase Stat1alpha activation.
We describe a novel mechanism of signaling interaction through which tumor necrosis factor-alpha (TNF-alpha) treatment augments interferon-gamma (IFN-gamma)-induced Stat1alpha DNA-binding complexes and transcriptional activation of a Stat-binding element. In TNF-alpha-treated cells, IFN-gamma-induced phosphorylation of Jak2 kinase is increased, Jak2 kinase activity is enhanced, and genetic studies indicate that TNF-alpha requires Jak2 kinase activity to enhance Stat1alpha tyrosine phosphorylation. Increased Jak2 and Stat1alpha phosphorylation are observed within minutes of coexposure to TNF-alpha/IFN-gamma, suggesting a direct signaling interaction. IFN-gamma receptor chain 1 (IFNGR-1) tyrosine phosphorylation is markedly enhanced in cells 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 processes.
Han
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Y
Department of Neurosciences, The Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.
Rogers
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N
Ransohoff
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RM
D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000494:pharmacology*; D053614:Janus Kinase 2; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon / Q000187:drug effects*; D012694:Serine / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014443:Tyrosine / Q000032:analysis; D000096743:Interferon gamma Receptor
D004268:DNA-Binding Proteins; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma; D053614:Janus Kinase 2; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon; D012694:Serine; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D000096743:Interferon gamma Receptor; C079868:gamma interferon activation factor; C507924:JAK2 protein, human