Long-term dietary antioxidant supplementation reduces production of selected inflammatory mediators by murine macrophages

Although macrophage (M phi)-derived compounds, including proinflammatory cytokines, prostaglandins (PG), and nitric oxide (NO), play important roles in host defense, excessive or inappropriate production of them has been implicated in the pathogenesis of a variety of inflammatory diseases. Aging is also associated with increased production of M phi compounds involved in inflammation. Short term dietary supplementation with selected antioxidants, such as glutathione (GSH) and vitamin E (E), has been shown to reduce age-related changes in M phi production of inflammatory compounds, but information is limited regarding the effects of long-term supplementation. Nor is information available on other less studied compounds with antioxidant properties, such as melatonin, strawberry extract, or combinations of compounds such as E + GSH. Therefore, we sought to determine if long term, from middle to old age, dietary supplementation of C57BL/6NCrlBR mice with E, GSH, E + GSH, melatonin or strawberry extract could modify age related changes in M phi production of pro- and antiinflammatory compounds. Eighteen-month-old C57BL/6NCrlBR mice were fed one of the following six semi-synthetic diets for 6 months: 1) control (30 ppm vitamin E), 2) vitamin E supplemented (control + 470 ppm vitamin E), 3) glutathione (GSH) supplemented (control + 0.5% glutathione), 4) vitamin E and glutathione supplemented (control + 470 ppm vitamin E + 0.5% glutathione), 5) melatonin supplemented (control + 11 ppm melatonin), or 6) strawberry extract supplemented (control + 1% strawberry extract). Supplementation with vitamin E or melatonin, but not GSH, E + GSH, or strawberry extract, reduced (p<0.05) unstimulated IL-6 and PGE(2) production by peritoneal M phi. Because PGE(2) has been shown to modulate IL-6 production, the reduction in PGE, production by vitamin E and melatonin may be partially responsible for the reduction in unstimulated IL-6 production. LPS stimulation resulted in production of IL-1 beta, IL-6, IL-10, IL-12, IL-15, NO, PGE(2), and TNF-alpha by peritoneal or bone marrow (BM)-derived M phi. Of these, only NO production was modulated by antioxidant supplementation and then significantly by vitamin E only. Vitamin E supplementation reduced the age-related increase in inducible NO production by peritoneal M phi (p<0.05), but not by BM M phi. In conclusion, vitamin E modulated production of at least three, and melatonin modulated production of at least two, molecules produced by M phi, which are involved in a variety of age-associated chronic and acute inflammatory diseases. Further research is needed to determine the mechanisms and clinical benefits of E and melatonin-induced reduction in M phi, inflammatory mediator production. (C) 2000 Elsevier Science Inc.