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Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways
T K Sengupta1, E M Schmitt, L B Ivashkiv
1Department of Medicine, Hospital for Special Surgery, New York, NY 10021, USA.
Abstract:
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.
Insights
Distinct signaling pathways can inhibit the JAK-STAT pathway, crucial for cytokine regulation. This crosstalk offers new strategies for modulating immune responses and inflammation.
Area of Science:
- Immunology
- Cellular Signaling
- Molecular Biology
Background:
- Cytokines regulate cell growth and differentiation via the JAK-STAT signaling pathway.
- Cytokine receptor ligation activates Jak kinases and STAT transcription factors, leading to nuclear translocation.
Purpose of the Study:
- To investigate the interruption of cytokine-triggered JAK-STAT signals by distinct signaling molecules.
- To explore potential therapeutic strategies for modulating cytokine activity.
Main Methods:
- Interruption of JAK-STAT signaling using cAMP, ionomycin, and GM-CSF.
- Assessing inhibition of Jak1 kinase activity, IL-6-induced gene activation, and STAT phosphorylation/DNA-binding.
- Analyzing the association of Jak1 with SH2-containing phosphatase 2.
Main Results:
- cAMP, ionomycin, and GM-CSF inhibited JAK-STAT signaling components, including Jak1 activity and STAT phosphorylation/DNA-binding.
- Interferon gamma-induced activation of Jak1 and Stat1 was also inhibited.
- Both ionomycin and GM-CSF increased Jak1 association with SH2-containing phosphatase 2, suggesting a mechanism of inhibition.
Conclusions:
- Crosstalk between distinct signaling pathways effectively inhibits JAK-STAT signal transduction.
- These findings suggest novel approaches for modulating cytokine activity in immune and inflammatory conditions.