Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine involved in multiple sclerosis (MS) pathogenesis. Adenosine, working through specific subtypes of cell surface adenosine receptors can inhibit TNF-α release. In this study, we determined the extent to which activation of adenosine A1 receptors reduced the secretion of TNF-α from U937 cells and peripheral blood mononuclear cells (PBMCs) from control (n=8) and MS patients (n=8). U937 cells and PBMCs were stimulated with a phorbol-12-myristate-13-acetate (PMA) and phytohemagglutinin (PHA) (5 ng/10μg/ml) for 4 h. and TNF-α levels were measured by ELISA. In U937 cells, the adenosine A1 receptor agonist R-phenylisopropyladenosine (RPIA) dose-dependently reduced TNF-α levels (IC50 100 nM) by up to 78±9% at 1μM; the reduction was blocked with the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). RPIA significantly (p<0.007) reduced TNF-α levels by 50±8% in PBMCs from controls but not in PBMCs from MS patients (13±9%). DPCPX blocked the RPIA-mediated inhibition of PBMC TNF-α synthesis. The diminished inhibition of TNF-α release by RPIA in PBMCs from MS patients was not due to reduced A1 receptor levels since immunoblots showed no differences between control and MS PBMCs samples. Desensitization of adenosine A1 receptors in PBMCs of MS patients may lead to higher serum levels of TNF-α and increased inflammatory responses.
|Original language||English (US)|
|State||Published - Mar 20 1998|
ASJC Scopus subject areas
- Molecular Biology