title: STAT3 regulates monocyte TNF-alpha production in systemic inflammation caused by cardiac surgery with cardiopulmonary bypass.
abstract: BACKGROUND
  Cardiopulmonary bypass (CPB) surgery initiates a controlled systemic inflammatory response characterized by a cytokine storm, monocytosis and transient monocyte activation. However, the responsiveness of monocytes to Toll-like receptor (TLR)-mediated activation decreases throughout the postoperative course. The purpose of this study was to identify the major signaling pathway involved in plasma-mediated inhibition of LPS-induced tumor necrosis factor (TNF)-α production by monocytes.
  
  
  RESULTS
  Pediatric patients that underwent CPB-assisted surgical correction of simple congenital heart defects were enrolled (n = 38). Peripheral blood mononuclear cells (PBMC) and plasma samples were isolated at consecutive time points. Patient plasma samples were added back to monocytes obtained pre-operatively for ex vivo LPS stimulations and TNF-α and IL-6 production was measured by flow cytometry. LPS-induced p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB activation by patient plasma was assessed by Western blotting. A cell-permeable peptide inhibitor was used to block STAT3 signaling. We found that plasma samples obtained 4 h after surgery, regardless of pre-operative dexamethasone treatment, potently inhibited LPS-induced TNF-α but not IL-6 synthesis by monocytes. This was not associated with attenuation of p38 MAPK activation or IκB-α degradation. However, abrogation of the IL-10/STAT3 pathway restored LPS-induced TNF-α production in the presence of suppressive patient plasma.
  
  
  CONCLUSIONS
  Our findings suggest that STAT3 signaling plays a crucial role in the downregulation of TNF-α synthesis by human monocytes in the course of systemic inflammation in vivo. Thus, STAT3 might be a potential molecular target for pharmacological intervention in clinical syndromes characterized by systemic inflammation.
authors.affiliation: Department of Pediatric Intensive Care, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Petrus R
authors.initials: PR
authors.lastname: de Jong
authors.forename: Alvin W L
authors.initials: AW
authors.lastname: Schadenberg
authors.forename: Theo
authors.initials: T
authors.lastname: van den Broek
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Beekman
authors.forename: Femke
authors.initials: F
authors.lastname: van Wijk
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
authors.forename: Berent J
authors.initials: BJ
authors.lastname: Prakken
authors.forename: Nicolaas J G
authors.initials: NJ
authors.lastname: Jansen
mesh_terms: D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D002648:Child; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000097:blood / Q000209:etiology / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000097:blood / Q000276:immunology*; D015398:Signal Transduction; D013903:Thoracic Surgery / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases