Dysregulation of adenosine A1 receptor-mediated cytokine expression in peripheral blood mononuclear cells from...

Cytokines, including tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6), have been implicated in the pathogenesis of multiple sclerosis (MS). The production and release of these cytokines are regulated in part by specific purinergic (adenosine) cell surface receptors. To determine the extent to which the adenosine A1 receptor influenced cytokine expression in peripheral blood mononuclear cells (PBMCs) from MS and control patients, we measured plasma adenosine and TNF alpha levels, A1 receptor messenger RNA (mRNA) and protein amounts, and the effects of activation of A1 receptors on TNF alpha and IL-6 production by PBMCs. Plasma levels of TNF alpha were significantly higher and adenosine levels were significantly lower in MS patients compared with control subjects. Levels of TNF alpha and IL-6 in mitogen-stimulated PBMC culture supernatants from MS patients or control patients were similar. Conversely, treatment of PBMCs with the adenosine A1 receptor agonist R-phenylisopropyladenosine (R-PIA) (1 microM) significantly inhibited mitogen-stimulated production of TNF alpha but not IL-6 in control subjects and significantly inhibited production of IL-6 but not TNF alpha in MS patients. The effects of R-PIA were selectively blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). A1 receptor protein levels were decreased significantly in PBMCs from MS patients. Taken together, these results suggest that decreased levels of adenosine and its A1 receptor modulate TNF alpha and IL-6 levels and may contribute to the pathogenesis of MS.