ADENOSINE MODULATION OF TUMOR NECROSIS FACTOR-ALPHA-INDUCED NEUTROPHIL ACTIVATION

We hypothesized that adenosine, known to be released from inflammatory sites, could lessen the potentially damaging activity of neutrophils (PMN) primed by tumor necrosis factor-alpha (TNF alpha) at sites of in fection. We investigated the effect of adenosine on PMN primed with ce ll-free medium from mononuclear leukocytes (MNL) that had been treated with lipopolysaccharide (LPS) yielding a conditioned medium rich in T NF alpha and on PMN primed with recombinant human TNF alpha (rhTNF alp ha). LPS (10 ng/mL) minimally primed PMN, but LPS-MNL-conditioned medi um increased PMN chemiluminescence in response to f-Met-Leu-Phe (fMLP) 1242% compared with unprimed PMN. LPS-MNL-conditioned medium containe d adenosine (similar to 30 nM). Converting the adenosine in the LPS-MN L-conditioned medium to inosine with adenosine deaminase (ADA) or bloc king adenosine binding to PMN with the adenosine receptor antagonist 1 ,3-dipropyl-8-(phenyl-p-acrylate)xanthine (BW A1433U) resulted in a ne ar doubling of chemiluminescence. The LPS-MNL-conditioned medium conta ined TNF alpha (836 pg/mL; similar to 1 U/mL). Recombinant human TNF a lpha (1 U/mL) primed PMN for a 1033% increase in chemiluminescence. Ad ded adenosine decreased rhTNF alpha-primed PMN chemiluminescence (IC50 similar to 100 nM), and adenosine (100 nM) decreased both superoxide and myeloperoxidase release from rhTNF alpha-primed fMLP stimulated PM N. The activity of adenosine was counteracted by ADA and BW A1433U, an d the modulating effect of adenosine was on the primed response rather than on priming per se. Thus, physiological concentrations of adenosi ne reduce the effects of recombinant human TNF alpha and native human TNF alpha (released from LPS-treated MNL) on PMN activity. Endogenous adenosine may preclude or minimize damage to infected tissue by dampin g the TNF alpha-primed PMN oxidative response.