Abstract
Abstract Numerous studies demonstrate the anti-inflammatory effects of cholinergic agonists, including nicotine. Investigations by our laboratory reveal that cholinergic stimulation inhibits endothelial cell activation, in part, through the NF-κB pathway. Monocyte chemoattractant protein-1 (MCP-1) is produced by endothelial cells and is a target of the JAK/STAT3 pathway. Human umbilical vein endothelial cells (HuVECs) were isolated and used to investigate the potential role of the JAK/STAT3 pathway in regulating MCP-1 production by activated endothelial cells following cholinergic stimulation. LPS induced MCP-1 expression in a dose-dependent manner. Soluble IL-6 receptor (IL-6sR), but not IL-6 itself induced significant MCP-1 expression. MCP-1 production following LPS or IL-6sR stimulation was mediated, in part, through the JAK/STAT3 pathway. Cholinergic agonists, nicotine and GTS-21, significantly reduced both LPS and IL-6sR-induced MCP-1 production. Cholinergic agonists also attenuated STAT3 phosphorylation following LPS and IL-6 stimulation. Finally, IL-6 blockade partially inhibits LPS-stimulated MCP-1 production and STAT3 phosphorylation. Together, our observations show that both LPS and IL-6sR induce MCP-1 production in endothelial cells, in part, through the JAK/STAT3 pathway that is inhibited by cholinergic mediators. This work was supported by NIH NIGMS R01GM070727-02.
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