Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways.
An important component of cytokine regulation of cell growth and differentiation is rapid transcriptional activation of genes by the JAK-STAT (signal transducer and activator of transcription) signaling pathway. Ligation of cytokine receptors results in tyrosine phosphorylation and activation of receptor-associated Jak protein tyrosine kinases and cytoplasmic STAT transcription factors, which then translocate to the nucleus. We describe the interruption of cytokine triggered JAK-STAT signals by cAMP, the calcium ionophore ionomycin, and granulocyte/macrophage colony-stimulating factor. Jak1 kinase activity, interleukin 6-induced gene activation, Stat3 tyrosine phosphorylation, and DNA-binding were inhibited, as was activation of Jak1 and Stat1 by interferon gamma. The kinetics and requirement for new RNA and protein synthesis for inhibition of interleukin 6 by ionomycin and GM-CSF differed, but both agents increased the association of Jak1 with protein tyrosine phosphatase ID (SH2-containing phosphatase 2). Our results demonstrate that crosstalk with distinct signaling pathways can inhibit JAK-STAT signal transduction, and suggest approaches for modulating cytokine activity during immune responses and inflammatory processes.
Sengupta
T K
TK
Department of Medicine, Hospital for Special Surgery, New York, NY 10021, USA.
Schmitt
E M
EM
Ivashkiv
L B
LB
D015152:Blotting, Northern; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D015759:Ionomycin / Q000494:pharmacology; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D054648:Protein Phosphatase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D000093242:Interleukin-6 Inhibitors
D000242:Cyclic AMP; D003513:Cycloheximide; D016207:Cytokines; D004247:DNA; D004268:DNA-Binding Proteins; D003609:Dactinomycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D047908:Intracellular Signaling Peptides and Proteins; D015759:Ionomycin; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D054648:Protein Phosphatase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D012313:RNA; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000093242:Interleukin-6 Inhibitors; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C507904:JAK1 protein, human; C507933:JAK3 protein, human; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human