Advanced glycation end products and lipopolysaccharide synergistically stimulate proinflammatory cytokine/chemokine production in endothelial cells via activation of both mitogen-activated protein kinases and nuclear factor-kappaB.
It has been well documented that both endogenous inflammatory mediator advanced glycation end products (AGEs) and exogenous inflammatory inducer lipopolysaccharide play key roles in the initiation and development of inflammatory diseases. However, the combined inflammation-stimulatory effect of AGEs and lipopolysaccharide on endothelial cells, and, furthermore, the underlying signal transduction pathways involved, have not been fully elucidated. We found that in vitro co-stimulation with AGE-human serum albumin (HSA) and lipopolysaccharide exhibits a synergistic effect on proinflammatory cytokine/chemokine interleukin-6, interleukin-8 and monochemoattractant protein-1 production in human umbilical vein endothelial cells. Similar to lipopolysaccharide, AGE-HSA stimulation induced mitogen-activated protein kinase phosphorylation and nuclear factor-kappaB nuclear translocation in human umbilical vein endothelial cells, which was further enhanced by a combination of the two stimulants. Pharmacological inhibitions of each individual signaling pathway, including p38, extracellular signal-regulated kinase 1/2, Jun N-terminal kinase and nuclear factor-kappaB, revealed that activation of all of these four pathways is necessary for the effective induction of interleukin-6, interleukin-8 and monochemoattractant protein-1 by both AGE-HSA and lipopolysaccharide. These results suggest that AGEs and lipopolysaccharide cooperatively induce proinflammatory cytokine/chemokine production by activating mitogen-activated protein kinases and nuclear factor-kappaB in endothelial cells, thus amplifying the inflammatory response and resulting in tissue damage.
Liu
Jinghua
J
Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China.
Zhao
Shanchao
S
Tang
Jing
J
Li
Zhijie
Z
Zhong
Tianyu
T
Liu
Yawei
Y
Chen
Dengyu
D
Zhao
Mingzhe
M
Li
Yusheng
Y
Gong
Xiaowei
X
Deng
Peng
P
Wang
Jiang H
JH
Jiang
Yong
Y
D021581:Active Transport, Cell Nucleus; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D004357:Drug Synergism; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D012709:Serum Albumin / Q000494:pharmacology*; D000075462:Serum Albumin, Human; D015398:Signal Transduction
D018925:Chemokines; D016207:Cytokines; D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012709:Serum Albumin; C109748:advanced glycation end products-human serum albumin; D020928:Mitogen-Activated Protein Kinases; D000075462:Serum Albumin, Human