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Th1 Cytokines Regulate Adenosine Receptors and Their Downstream Signaling Elements in Human Microvascular Endothelial Cells ¹

Divisions of Clinical Pharmacology and Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY 10016

We and others have shown that adenosine, acting at its receptors, is a potent modulator of inflammation and angiogenesis. To better understand the regulation of adenosine receptors during these processes we studied the effects of IL-1, TNF-, and IFN- on expression and function of adenosine receptors and select members of their coupling G proteins in human dermal microvascular endothelial cells (HMVEC). HMVEC expressed message and protein for A_2A and A_2B, but not A₁ or A₃ receptors. IL-1 and TNF- treatment increased message and protein expression of A_2A and A_2B receptor. IFN- treatment also increased the expression of A_2B receptors, but decreased expression of A_2A receptors. Resting HMVEC and IFN--treated cells showed minimal cAMP response to the selective A_2A receptor agonist 2-[2-(4-chlorophenyl)ethoxy]adenosine (MRE0094). In contrast, MRE0094 stimulated a dose-dependent increase in cAMP levels in TNF--treated cells that was almost completely blocked by the A_2A receptor antagonist ZM-241385 (4-{2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol). The nonselective adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine increased cAMP levels in both TNF-- and IFN--treated cells, but not control cells, and its effect was only partially reversed by ZM-241385 in TNF--treated cells and not affected in IFN--treated cells. HMVEC expressed a higher level of G protein 1 isoform than 4 isoform. Although none of the cytokines tested affected G₁ expression, both IL-1 and TNF- significantly up-regulated G₄ expression. These findings indicate that inflammatory cytokines modulate adenosine receptor expression and function on HMVECs and suggest that the interaction between proinflammatory cytokines and adenosine receptors may affect therapeutic responses to anti-inflammatory drugs that act via adenosine-dependent mechanisms.

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