Age-Associated Alterations in Splenic iNOS Regulation: Influence of Constitutively Expressed IFN-γ and Correction Following Supplementation with PPARα Activators or Vitamin E

Alterations in transcription factor activities in aged mice may lead to the production of many inflammatory molecules in the absence of exogenous stimulation. Splenocytes from 22-month-old female C57BL/6 mice are dysregulated in their capacity to control the inducible nitric oxide synthase gene as a result of elevations in the endogenous levels and activity of interferon (IFN)-γ. Splenocytes from aged mice produced high levels of IFN-γ in vitro and active STAT-1 was found in nuclear extracts from these splenocytes. Administration to aged mice of neutralizing antibodies against IFN-γ imposed appropriate regulation over nitric oxide production by stimulated splenocytes. Reestablishment of normal redox balance following dietary supplementation of aged mice with activators of the peroxisome proliferator-activated receptor α or the antioxidant α-tocopherol (vitamin E) restored appropriate regulation over both the production of IFN-γ and the secretion of nitric oxide.