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

Lookup NU author(s): Dr Diego Miranda Saavedra

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Abstract

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.

Publication metadata

Author(s): Pike KA, Hutchins AP, Vinette V, Theberge JF, Sabbagh L, Tremblay ML, Miranda-Saavedra D

Publication type: Article

Publication status: Published

Journal: Science Signaling

Year: 2014

Volume: 7

Issue: 324

Print publication date: 06/05/2014

ISSN (print): 1945-0877

ISSN (electronic): 1937-9145

Publisher: AAAS

URL: http://dx.doi.org/10.1126/scisignal.2005020

DOI: 10.1126/scisignal.2005020

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