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Am J Physiol Cell Physiol 297: C1294-C1306, 2009. First published September 9, 2009; doi:10.1152/ajpcell.00160.2009
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Vascular Biology

Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation

Prodyot K. Chatterjee,1,2 Yousef Al-Abed,2 Barbara Sherry,1 and Christine N. Metz1,2

1The Center for Immunology and Inflammation and 2The Center for Patient-Oriented Research, The Feinstein Institute for Medical Research, Manhasset, New York

Submitted 10 April 2009 ; accepted in final form 7 September 2009

The cholinergic anti-inflammatory pathway is a physiological mechanism that inhibits cytokine production and minimizes tissue injury during inflammation. Previous investigations revealed that cholinergic stimulation (via cholinergic agonists and vagus nerve stimulation) suppresses endothelial cell activation and leukocyte recruitment. The purpose of this study was to investigate the mechanisms by which cholinergic agonists (e.g., nicotine and GTS-21) regulate endothelial cell activation. Specifically, we examined the effects of cholinergic agonists on IL-6-mediated endothelial cell activation through the JAK2/STAT3 signaling pathway. Treatment of macrovascular human umbilical vein endothelial cells (HUVECs) and microvascular endothelial cells (MVECs) with the cholinergic agonists nicotine and GTS-21 significantly reduced IL-6-mediated monocyte chemoattractant protein-1 (MCP-1) production and ICAM-1 expression which are regulated through the JAK2/STAT3 pathway. We found that treatment of endothelial cells with cholinergic agonists significantly reduced STAT3 activation by phosphorylation and DNA binding. The inhibition of STAT3 phosphorylation was reversed by sodium orthovanadate, an inhibitor of tyrosine phosphatases, as well as by NSC-87877 suggesting a SHP1/2-dependent mechanism. Further investigations showed that cholinergic agonists reduced the phosphorylation of JAK2, an upstream component of the JAK2/STAT3 pathway. Finally, we observed that nicotine and GTS-21 treatment decreased levels of SOCS3 (suppressor of cytokine signaling; a regulator of the inflammatory activity of IL-6) in activated endothelial cells. These data demonstrate that cholinergic agonists suppress IL-6-mediated endothelial cell activation through the JAK2/STAT3 pathway. Our results have significant implications for better understanding the therapeutic potential of cholinergic agonists for treating IL-6 mediated inflammatory conditions.

interleukin-6; soluble interleukin-6 receptor; monocyte chemoattractant protein-1; intercellular adhesion molecule-1; suppressor of cytokine signaling 3; inflammation; nicotine; GTS-21


Address for reprint requests and other correspondence: C. N. Metz, Laboratory of Medicinal Biochemistry, The Susan and Herman Merinoff Center for Patient Oriented Research, 350 Community Dr., Manhasset, NY 11030 (e-mail: cmetz{at}nshs.edu).






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