title: A novel pro-inflammatory mechanism of action of resistin in human endothelial cells: up-regulation of SOCS3 expression through STAT3 activation.
abstract: Resistin is a significant local and systemic regulatory cytokine involved in inflammation. Suppressors of cytokine signaling (SOCS) proteins are intracellular regulators of receptor signal transduction induced by several cytokines in a cytokine and cell specific manner. Resistin up-regulates SOCS3 expression in mice adipocytes but it is not known whether this is a common occurrence in other cells. We questioned whether resistin-induces SOCS3 in human endothelial cells and if signal transducer and activator of transcription (STAT) proteins are involved in the process. The Real-Time PCR and Western blot analysis showed that in resistin-activated HEC the gene and protein expression of SOCS3 were significantly increased. Furthermore, resistin induced activation of STAT3 as characterized by increased tyrosine phosphorylation. Resistin-induced SOCS3 expression was blocked by specific inhibitors of STAT3 signaling and by the transfection of siRNA specific for STAT3. Silencing of SOCS3 gene expression by transfection with SOCS3 siRNA reduced the expression of resistin induced-P-selectin and fractalkine in HEC. Together, our results demonstrate that in HEC (1) resistin up-regulates SOCS3 expression and activates STAT3 transcription factor; (2) the increase in SOCS3 mRNA and protein expression as well as STAT3 activation have a long-lasting effect (up to 18h); (3) inhibition of SOCS3 function prevents resistin-induced expression of cell adhesion molecules P-selectin and fractalkine and thus activation of endothelial cells. The data uncover a new resistin-mediated mechanism in human endothelial cells and designate SOCS3 as a novel therapeutic target to modulate resistin-dependent inflammation in vessel wall diseases.
authors.affiliation: Institute of Cellular Biology and Pathology Nicolae Simionescu of the Romanian Academy, 8 B.P. Hasdeu Street, 050568 Bucharest, Romania.
authors.forename: Monica
authors.initials: M
authors.lastname: Pirvulescu
authors.forename: Ileana
authors.initials: I
authors.lastname: Manduteanu
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gan
authors.forename: Daniela
authors.initials: D
authors.lastname: Stan
authors.forename: Viorel
authors.initials: V
authors.lastname: Simion
authors.forename: Elena
authors.initials: E
authors.lastname: Butoi
authors.forename: Manuela
authors.initials: M
authors.lastname: Calin
authors.forename: Maya
authors.initials: M
authors.lastname: Simionescu
mesh_terms: D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D052243:Resistin / Q000494:pharmacology / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000819:agonists / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D052243:Resistin; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins