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Adenosine Regulates the Proinflammatory Signaling Function of Thrombin in Endothelial Cells
Author(s) -
Hassanian Seyed Mahdi,
Dinarvand Peyman,
Rezaie Alireza R.
Publication year - 2014
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24568
Subject(s) - proinflammatory cytokine , adenosine , thrombin , microbiology and biotechnology , chemistry , chemokine , adenosine a3 receptor , adenosine receptor , adenosine a2b receptor , inflammation , purinergic signalling , receptor , agonist , biology , biochemistry , immunology , platelet
The plasma level of the regulatory metabolite adenosine increases during the activation of coagulation and inflammation. Here we investigated the effect of adenosine on modulation of thrombin‐mediated proinflammatory responses in HUVECs. We found that adenosine inhibits the barrier‐disruptive effect of thrombin in HUVECs by a concentration‐dependent manner. Analysis of cell surface expression of adenosine receptors revealed that A 2A and A 2B are expressed at the highest level among the four receptor subtypes (A 2B > A 2A > A 1 > A 3 ) on HUVECs. The barrier‐protective effect of adenosine in response to thrombin was recapitulated by the A 2A specific agonist, CGS 21680, and abrogated both by the siRNA knockdown of the A 2A receptor and by the A 2A ‐specific antagonists, ZM‐241385 and SCH‐58261. The thrombin‐induced RhoA activation and its membrane translocation were both inhibited by adenosine in a cAMP‐dependent manner, providing a molecular mechanism through which adenosine exerts a barrier‐protective function. Adenosine also inhibited thrombin‐mediated activation of NF‐κB and decreased adhesion of monocytic THP‐1 cells to stimulated HUVECs via down‐regulation of expression of cell surface adhesion molecules, VCAM‐1, ICAM‐1, and E‐selectin. Moreover, adenosine inhibited thrombin‐induced elevated expression of proinflammatory cytokines, IL‐6 and HMGB‐1; and chemokines, MCP‐1, CXCL‐1, and CXCL‐3. Taken together, these results suggest that adenosine may inhibit thrombin‐mediated proinflammatory signaling responses, thereby protecting the endothelium from injury during activation of coagulation and inflammation. J. Cell. Physiol. 229: 1292–1300, 2014. © 2014 Wiley Periodicals, Inc.