title: Protein tyrosine phosphatase 1B is a regulator of the interleukin-10-induced transcriptional program in macrophages.
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-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.
authors.affiliation: 1Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Pike
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Hutchins
authors.forename: Valerie
authors.initials: V
authors.lastname: Vinette
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Théberge
authors.forename: Laurent
authors.initials: L
authors.lastname: Sabbagh
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Diego
authors.initials: D
authors.lastname: Miranda-Saavedra
mesh_terms: D000818:Animals; D016753:Interleukin-10 / Q000502:physiology*; D053662:Interleukin-4 Receptor alpha Subunit / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D053662:Interleukin-4 Receptor alpha Subunit; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse