Research ArticleImmunology

Protein Tyrosine Phosphatase 1B Is a Regulator of the Interleukin-10–Induced Transcriptional Program in Macrophages

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Sci. Signal.  06 May 2014:
Vol. 7, Issue 324, pp. ra43
DOI: 10.1126/scisignal.2005020

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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-type macrophages, as was the IL-10–dependent increase in the cell surface expression of the anti-inflammatory cytokine receptor IL-4Rα. 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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