期刊
PLOS ONE
卷 7, 期 4, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0035070
关键词
-
资金
- Wilhelmina Children's Hospital Research Fund
- Alexandre Suerman MD/PhD Program of the University Medical Center Utrecht
- Dutch Organization for Scientific Research (NWO VIDI)
- Dutch Arthritis Foundation
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)-alpha 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-alpha and IL-6 production was measured by flow cytometry. LPS-induced p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappa 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-alpha but not IL-6 synthesis by monocytes. This was not associated with attenuation of p38 MAPK activation or I kappa B-alpha degradation. However, abrogation of the IL-10/STAT3 pathway restored LPS-induced TNF-alpha 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-alpha 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据