STAT3 regulates monocyte TNF-alpha production in systemic inflammation caused by cardiac surgery with cardiopulmonary bypass

• Published in: PloS one Vol. 7; no. 4; p. e35070
• Main Authors: de Jong, Petrus R, Schadenberg, Alvin W L, van den Broek, Theo, Beekman, Jeffrey M, van Wijk, Femke, Coffer, Paul J, Prakken, Berent J, Jansen, Nicolaas J G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.04.2012; Public Library of Science (PLoS)
• Subjects: Biology; Biomarkers; Cardiopulmonary Bypass - adverse effects; Cardiovascular disease; Cell activation; Chemokines; Child; Children & youth; Congenital diseases; Congenital heart defects; Coronary artery bypass; Cytokines; Cytometry; Dexamethasone; Female; Flow cytometry; Heart; Heart diseases; Heart surgery; Humans; I-kappa B Kinase - immunology; I-kappa B Kinase - metabolism; Immune system; Immunity, Innate - immunology; Immunoassay; Immunology; Inflammation; Inflammation - blood; Inflammation - etiology; Inflammation - immunology; Inflammatory response; Inhibition; Intensive care; Interleukin 10; Interleukin 6; Interleukin-10 - immunology; Interleukin-10 - metabolism; Interleukin-6 - immunology; Interleukin-6 - metabolism; Ischemia; Leukocytes (mononuclear); Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Male; MAP kinase; Medicine; Mitogens; Monocytes; Monocytes - drug effects; Monocytes - immunology; Monocytes - metabolism; Monocytosis; Neutrophils; NF-kappa B - immunology; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - immunology; p38 Mitogen-Activated Protein Kinases - metabolism; Pediatrics; Peptide inhibitors; Peripheral blood mononuclear cells; Pharmacology; Protein kinase; Proteins; Rheumatoid arthritis; Rodents; Signal Transduction; Signaling; Stat3 protein; STAT3 Transcription Factor - blood; STAT3 Transcription Factor - immunology; Surgery; Synthesis; Thoracic Surgery - methods; Toll-like receptors; Tumor necrosis factor; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - immunology; Tumor necrosis factor-α; Western blotting; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0035070

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. 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. 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.