TLR4 activation induces nontolerant inflammatory response in endothelial cells.
In professional immune cells, Toll-like receptor 4 (TLR4) induces tightly regulated inflammatory response to avoid tissue damage via the induction of "endotoxin tolerance", which is a transient state of cell desensitization in response to lipopolysaccharide (LPS) restimulation after a prior LPS exposure. However, in endothelial cells, the regulation of TLR4-induced inflammation is not fully understood. In this study, we found that the gene transcripts for a lot of Toll-like receptors were expressed in various endothelial cells, including human umbilical vein endothelial cells (HUVEC), human aortic endothelial cell (HAEC), and mouse microvascular endothelial cells (bEND.3). Proteins of TLR4 and its coreceptor CD14 were also detected in HUVEC. LPS treatment significantly upregulated the expression of proinflammation cytokines such as IL-1β, IL-6, and IL-8 only in HUVEC, but not in HAEC and bEND.3, suggesting that vein endothelial cells are important source of proinflammatory cytokines in response to LPS. Unexpectedly, "endotoxin tolerance" was not induced in endothelial cell, but was induced in control glial cells, as LPS pretreatment downregulated the cytokine expression in control glial cells, but did not in endothelial cells, when the cells were restimulated with LPS. The upregulation of cytokine gene expression was dependent on NF-κB signaling, and NF-κB inhibitor repressed the induction of cytokines. Two important signal molecules MyD88 and TRIF, which are TLR4 downstream and NF-κB upstream, were upregulated in vein endothelial cells but were downregulated in control glial cells. These results suggested that vein endothelial cells may play important roles in the pathophysiology of systemic inflammation-associated diseases such as sepsis and septic cardiomyopathy.
Wang
Wenmeng
W
Department of Cardiology, Renmin Hospital of Wuhan University, No. 99, Ziyang Road, Wuhan, 430060, China.
Deng
Minjie
M
Liu
Xueting
X
Ai
Wen
W
Tang
Qizhu
Q
Hu
Jinyue
J
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000276:immunology* / Q000473:pathology; D004730:Endothelium, Vascular / Q000276:immunology; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000209:etiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009457:Neuroglia; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000032:analysis / Q000276:immunology* / Q000378:metabolism*
D016207:Cytokines; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4