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

PLoS One. 2012;7(4):e35070. doi: 10.1371/journal.pone.0035070. Epub 2012 Apr 10.


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.

Methodology/principal findings: 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/significance: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiopulmonary Bypass / adverse effects*
  • Child
  • Female
  • Humans
  • I-kappa B Kinase / immunology
  • I-kappa B Kinase / metabolism
  • Immunity, Innate / immunology
  • Inflammation / blood
  • Inflammation / etiology
  • Inflammation / immunology*
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Lipopolysaccharides / pharmacology
  • Male
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Monocytes / metabolism
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • STAT3 Transcription Factor / blood
  • STAT3 Transcription Factor / immunology*
  • Signal Transduction
  • Thoracic Surgery / methods
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / immunology
  • p38 Mitogen-Activated Protein Kinases / immunology
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • IL10 protein, human
  • IL6 protein, human
  • Interleukin-6
  • Lipopolysaccharides
  • NF-kappa B
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • I-kappa B Kinase
  • p38 Mitogen-Activated Protein Kinases