Chronic exercise increases macrophage-mediated tumor cytolysis in young and old mice

In this study, we determined the effects of age and chronic treadmill runni ng (16 wk; 5 days/wk; 45 min/day; 18-22 m/min) on resident peritoneal macro phage responsiveness to interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) in young (6 mo) and aged (22 mo) male BALB/cByJ mice by measuring cy tolytic ability and production of reactive nitrogen products. Macrophages ( >90% Mac-3(+)) were incubated with various concentrations of IFN-gamma and LPS for 24 h. After washing, P815 tumor cells were utilized as targets in a 16-h Cr-51, release assay. We found that aging resulted in a significant r eduction in the ability of macrophages to respond to the highest doses of I FN-gamma and LPS and kill P815 cells (46 +/- 4 vs. 34 +/- 2% in young and o ld mice, respectively). Exercise training significantly increased macrophag e cytolysis in both age groups (66 + 7 vs. 44 + 2% in young and old mice, r espectively); this effect was larger in the young mice. Macrophages from yo ung exercised mice also produced significantly (50-60%) more NO2-; there wa s 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 e xercise-induced increases in these measures. RT-PCR analysis revealed signi ficantly higher iNOS mRNA levels in macrophages obtained from the exercise- trained mice and significantly lower iNOS mRNA in old compared with young m ice. We conclude that aging reduces and exercise training increases the cap acity of resident peritoneal macrophages to respond to IFN-gamma and LPS wi th increased tumor cytolysis. Enhanced iNOS gene expression and NO2- produc tion are likely the contributing mechanisms of the exercise-induced enhance ment of cytolysis in young mice. While L-NMMA did block the exercise-induce d increase in cytolysis, exercise did not increase NO2- or iNOS gene expres sion in the old mice, indicating perhaps the contribution of other cytolyti c mechanisms in old mice.