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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‐κB
Author(s) -
Liu Jinghua,
Zhao Shanchao,
Tang Jing,
Li Zhijie,
Zhong Tianyu,
Liu Yawei,
Chen Dengyu,
Zhao Mingzhe,
Li Yusheng,
Gong Xiaowei,
Deng Peng,
Wang Jiang H.,
Jiang Yong
Publication year - 2009
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2009.07165.x
Subject(s) - proinflammatory cytokine , microbiology and biotechnology , chemokine , p38 mitogen activated protein kinases , biology , protein kinase a , chemistry , kinase , inflammation , immunology
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‐κB 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‐κB, 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‐κB in endothelial cells, thus amplifying the inflammatory response and resulting in tissue damage.