A role for histamine in cytokine modulation by the adenosine A(3) receptor agonist, 2-Cl-IB-MECA

The effects of adenosine receptor agonists on cytokine production in vivo were investigated in mouse models of endotoxemia. Selective adenosine A(3) (2-chloro-N(6)-(3-iodobenzyl) adenosine-5'-N-methyluronamide) (2-Cl-IB-MECA) and A(2A) (2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride) (CGS 21860) receptor agonists were found to modulate endotoxin-induced cytokine responses in mice sensitized to D-galactosamine or primed with Corynebacterium parvum. The adenosine receptor agonists had similar effects in these models of endotoxemia, suppressing the production of tumor necrosis factor alpha (TNF-alpha) and interleukin-12 while enhancing that of interleukin-10. However, 2-Cl-IB-MECA also caused a dramatic increase in circulating histamine levels shortly after its injection into mice. The cytokine modulatory activities of 2-Cl-IB-MECA were mimicked by the mast cell depleting compound 48/80 and both drugs only produced such effects at doses that caused an elevation in circulating histamine levels. Furthermore, the capacity of 2-Cl-IB-MECA to modulate cytokine responses was greatly diminished when the drug was administered to mast cell deficient (WBB6F-W/W(V)) mice. Together, these results strongly suggest a role for histamine in cytokine modulation by 2-Cl-IB-MECA. Cimetidine, a histamine H(2) receptor antagonist, did not reverse cytokine modulation by 2-Cl-IB-MECA and pyrilamine, a histamine H(1) receptor antagonist, prevented the increase in serum histamine that was induced by 2-Cl-IB-MECA. This effect of pyrilamine and other histamine H(1) receptor antagonists confounded attempts to determine a role for the histamine H(1) receptor in cytokine modulation by 2-Cl-IB-MECA. However, under some experimental conditions, pyrilamine appeared to antagonize the modulatory effects of the adenosine A(3) receptor agonist on cytokine responses. The apparent antagonism of pyrilamine was unrelated to its suppressive effects on histamine release and appeared to reflect activity at the level of the histamine H(1) receptor.