Journal
SCIENCE SIGNALING
Volume 7, Issue 324, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2005020
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Funding
- Canadian Institute of Health Research [MOP-62887]
- Canadian Cancer Society [701788]
- Richard and Edith Strauss Foundation
- Medical Research Council (UK)
- Newcastle University Medical School
- Japan Society for the Promotion of Science through the WPI-IFReC Research Program
- KAKENHI grant
- Kishimoto Foundation
- ETH Zurich-Japan Science and Technology Agency (ETHZ-JST) Japanese-Swiss Cooperative Program
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Both pro- and anti-inflammatory cytokines activate the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway; however, they elicit distinct transcriptional programs. Posttranslational modifications of STAT proteins, such as tyrosine phosphorylation, are critical to ensure the differential expression of STAT target genes. Although JAK-STAT signaling is dependent on reversible tyrosine phosphorylation, whether phosphatases contribute to the specificity of STAT-dependent gene expression is unclear. We examined the role of protein tyrosine phosphatase 1B (PTP1B) in regulating the interleukin-10 (IL-10)-dependent, STAT3-mediated anti-inflammatory response. We found that IL-10-dependent STAT3 phosphorylation and anti-inflammatory gene expression were enhanced in macrophages from PTP1B(-/-) mice compared to those in macrophages from wild-type mice. Consistent with this finding, the IL-10-dependent suppression of lipopolysaccharide-induced macrophage activation was increased in PTP1B(-/-) macrophages compared to that in wild-typemacrophages, as was the IL-10-dependent increase in the cell surface expression of the anti-inflammatory cytokine receptor IL-4R alpha. Furthermore, RNA sequencing revealed the expression of genes encoding proinflammatory factors in IL-10-treated PTP1B(-/-) macrophages, which correlated with increased phosphorylation of STAT1, which is not normally highly activated in response to IL-10. These findings identify PTP1B as a central regulator of IL-10R-STAT3 and IL-10R-STAT1 signaling, and demonstrate that phosphatases can tailor the quantitative and qualitative properties of cytokine-induced transcriptional responses.
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