In this study, we determined the effects of age and chronic treadmill running (16 wk; 5 days/wk; 45 min/day; 18-22 m/min) on resident peritoneal macrophage responsiveness to interferon- (IFN-) and lipopolysaccharide (LPS) in young (6 mo) and aged (22 mo) male BALB/cByJ mice by measuring cytolytic ability and production of reactive nitrogen products. Macrophages (>90% Mac-3⁺) were incubated with various concentrations of IFN- and LPS for 24 h. After washing, P815 tumor cells were utilized as targets in a 16-h ⁵¹Cr release assay. We found that aging resulted in a significant reduction in the ability of macrophages to respond to the highest doses of IFN- and LPS and kill P815 cells (46 ± 4 vs. 34 ± 2% in young and old mice, respectively). Exercise training significantly increased macrophage cytolysis in both age groups (66 + 7 vs. 44 + 2% in young and old mice, respectively); this effect was larger in the young mice. Macrophages from young exercised mice also produced significantly (50-60%) more NO₂; there was a tendency for higher NO₂ in old exercisers. The inducible nitric oxide synthase (iNOS) inhibitor N^G-monomethyl-L-arginine (L-NMMA) significantly reduced macrophage cytolysis and NO₂ production and completely abrogated exercise-induced increases in these measures. RT-PCR analysis revealed significantly higher iNOS mRNA levels in macrophages obtained from the exercise-trained mice and significantly lower iNOS mRNA in old compared with young mice. We conclude that aging reduces and exercise training increases the capacity of resident peritoneal macrophages to respond to IFN- and LPS with increased tumor cytolysis. Enhanced iNOS gene expression and NO₂ production are likely the contributing mechanisms of the exercise-induced enhancement of cytolysis in young mice. While L-NMMA did block the exercise-induced increase in cytolysis, exercise did not increase NO₂ or iNOS gene expression in the old mice, indicating perhaps the contribution of other cytolytic mechanisms in old mice.

nitric oxide; inducible nitric oxide synthase; interferon-; lipopolysaccharide; immunity; aging

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