title: IFN gamma-dependent SOCS3 expression inhibits IL-6-induced STAT3 phosphorylation and differentially affects IL-6 mediated transcriptional responses in endothelial cells.
abstract: IL-6 has pro- and anti-inflammatory effects and is involved in endothelial cell (EC) dysfunction. The anti-inflammatory effects of IL-6 are mediated by signal transducer and activator of transcription-3 (STAT3), which is importantly controlled by suppressor of cytokine signaling 3 (SOCS3). Therefore, cytokines that modulate SOCS3 expression might inhibit the anti-inflammatory effects of IL-6. We hypothesized that in EC, interferon-gamma (IFNgamma)-induced SOCS3 expression leads to inhibition of IL-6-induced STAT3 activation and IL-6-dependent expression of anti-, but not pro-inflammatory, target genes. IFNgamma activated STAT1 and STAT3 and increased SOCS3 expression in EC. IL-6 only activated STAT3 and induced SOCS3 expression. IFNgamma pretreatment of EC inhibited IL-6-induced STAT3 activation accompanied by increased SOCS3 protein. Inhibition of SOCS3 expression, using costimulation, Act-D, and small interfering RNA (siRNA), subsequently implicated the importance of IFNgamma-induced SOCS3 in this phenomenon. Pretreatment of EC with IFNgamma also affected the transcriptional program induced by IL-6. We identified 1) IL-6 anti-inflammatory target genes that were inhibited by IFNgamma, 2) IFNgamma-target genes of pro-inflammatory nature that were increased in response to IL-6 in the presence of IFNgamma, and 3) a set of target genes that were increased upon IL-6 or IFNgamma alone, or combined IFNgamma and IL-6. In summary, by increasing SOCS3 expression in EC, IFNgamma can selectively inhibit STAT3-dependent IL-6 signaling. This in turn leads to decreased expression of some EC protective genes. In contrast, other genes of pro-inflammatory nature are not inhibited or even increased. This IFNgamma-induced shift in IL-6 signaling to a pro-inflammatory phenotype could represent a novel mechanism involved in EC dysfunction.
authors.affiliation: Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznan, Poland. johannes.bluijssen@amu.edu.pl
authors.forename: Hans A R
authors.initials: HA
authors.lastname: Bluyssen
authors.forename: M Mehdi
authors.initials: MM
authors.lastname: Rastmanesh
authors.forename: Chantal
authors.initials: C
authors.lastname: Tilburgs
authors.forename: Kim
authors.initials: K
authors.lastname: Jie
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Wesseling
authors.forename: Marie-Jose
authors.initials: MJ
authors.lastname: Goumans
authors.forename: Peter
authors.initials: P
authors.lastname: Boer
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
authors.forename: Branko
authors.initials: B
authors.lastname: Braam
mesh_terms: D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D000093242:Interleukin-6 Inhibitors
chemical_list: D018836:Inflammation Mediators; D007371:Interferon-gamma; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000093242:Interleukin-6 Inhibitors; C106644:SOCS3 protein, human