%0 Journal Article
%T STAT3 Regulates Monocyte TNF-Alpha Production in Systemic Inflammation Caused by Cardiac Surgery with Cardiopulmonary Bypass
%A Petrus R. de Jong
%A Alvin W. L. Schadenberg
%A Theo van den Broek
%A Jeffrey M. Beekman
%A Femke van Wijk
%A Paul J. Coffer
%A Berent J. Prakken
%A Nicolaas J. G. Jansen
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0035070
%X 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)-¦Á 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-¦Á and IL-6 production was measured by flow cytometry. LPS-induced p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-¦ÊB 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-¦Á but not IL-6 synthesis by monocytes. This was not associated with attenuation of p38 MAPK activation or I¦ÊB-¦Á degradation. However, abrogation of the IL-10/STAT3 pathway restored LPS-induced TNF-¦Á 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-¦Á 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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0035070