Age-associated alterations in splenic iNOS regulation: influence of constitutively expressed IFN-gamma and correction following supplementation with PPARalpha 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)-gamma. Splenocytes from aged mice produced high levels of IFN-gamma in vitro and active STAT-1 was found in nuclear extracts from these splenocytes. Administration to aged mice of neutralizing antibodies against IFN-gamma 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 alpha or the antioxidant alpha-tocopherol (vitamin E) restored appropriate regulation over both the production of IFN-gamma and the secretion of nitric oxide.
Poynter
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ME
Department of Pathology, University of Utah, Salt Lake City, Utah 84132, USA.
Daynes
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D000375:Aging / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism / Q000652:urine; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010084:Oxidation-Reduction; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000502:physiology; D050794:STAT1 Transcription Factor; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists* / Q000502:physiology; D014810:Vitamin E / Q000008:administration & dosage / Q000494:pharmacology*
D000906:Antibodies; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014810:Vitamin E; D009569:Nitric Oxide; D007371:Interferon-gamma; C006253:pirinixic acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse