STAT3 Regulates Monocyte TNF-Alpha Production in Systemic Inflammation Caused by Cardiac Surgery with Cardiopulmonary Bypass

Abstract

BackgroundCardiopulmonary 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 FindingsPediatric 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/SignificanceOur 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.

Protective effects of the melanocortin analog NDP-α-MSH in rats undergoing cardiac arrest

“…Accordingly, melanocortins have been repeatedly reported to reduce blood levels of oxygen-derived free radicals and nitric oxide under pre-terminal conditions such as myocardial ischemia/reperfusion, circulatory shock and respiratory arrest (Giuliani et al, 2007a;Guarini et al, 1996Guarini et al, , 1997aGuarini et al, , 1997bGuarini et al, , 1998Mioni et al, 2003Mioni et al, , 2005, that could likewise contribute to prevent organ damage in CA/CPR. The cardioprotective JAK/ERK/STAT signaling pathways are also thought to supervise the transcriptional regulation of several genes that modulate inflammation (Bolli et al, 2011;de Jong et al, 2012;Minamino, 2012;Obana et al, 2012;Ottani et al, 2013;Xuan et al, 2001Xuan et al, , 2005. Consistently, here we report that co-administration of epinephrine and NDP-α-MSH also reduces heart levels of the pro-inflammatory mediators TNF-α and IL-6, whereas increases those of the antiinflammatory cytokine IL-10.…”

Evaluation of the Relationship Between Plasma Transfusion and Nosocomial Infection After Cardiac Surgery in Children Younger Than 1 Year*

“…Furthermore, the statistical method used did not consider indication as a potential confounding factor (15). This result could be explained by the occurrence of SIRS after cardiac surgery under CPB, which induces important immunological changes (29,30). This result could be explained by the occurrence of SIRS after cardiac surgery under CPB, which induces important immunological changes (29,30).…”

Inhibition of endogenous heat shock protein 70 attenuates inducible nitric oxide synthase induction via disruption of heat shock protein 70/Na+/H+ exchanger 1‐Ca2+‐calcium‐calmodulin‐dependent protein kinase II/transforming growth factor β‐activated kinase 1‐nuclear factor‐κB signals in BV‐2 microglia

“…IKKγ is a regulatory component with no catalytic activity (Ammirante et al, ). IKKα is capable of limiting the occurrence of inflammatory responses (Song et al, ), whereas IKKβ has been shown to enhance inflammatory responses via promotion of IκB‐α phosphorylation and degradation (De Jong et al, ). This study shows a significant decrease in the LPS‐mediated phosphorylation of IKKβ in PES‐treated microglia, demonstrating that deactivation of IKKβ might mediate the effect of Hsp70 inhibition on iNOS induction.…”

“…Although disruption of Ca 2+ ‐IκB‐α–NF‐κB signals has been proved to mediate the effect of Hsp70 inhibition on iNOS induction (Huang et al, ), the linkage between Ca 2+ and IκB‐α degradation has not been characterized. It is well known that IκB‐α degradation is initiated by IκB kinase β (IKKβ; De Silva et al, ; De Jong et al, ; Liu et al, ), whose activity is controlled by its upstream kinases, such as Ca 2+ ‐calmodulin‐dependent protein kinase II (CaMKII) and transforming growth factor β‐activated kinase 1 (TAK1; Hughes et al, ; Moreno‐García et al, ). CaMKII has been shown to mediate the activation of TAK1.…”