by Petrus R. de Jong, Alvin W. L. Schadenberg, Theo van den Broek, Jeffrey M. Beekman, Femke van Wijk, Paul J. Coffer, Berent J. Prakken, Nicolaas J. G. Jansen
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)-a 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-a and IL-6 production was measured by flow cytometry. LPS-induced p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-?B 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-a but not IL-6 synthesis by monocytes. This was not associated with attenuation of p38 MAPK activation or I?B-a degradation. However, abrogation of the IL-10/STAT3 pathway restored LPS-induced TNF-a 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-a 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.