Macrophage hypo-responsiveness to interferon-γ in aged mice is associated with impaired signaling through Jak-STAT

Since macrophages (Mφs) are a first line of defense against pathogens, and are involved in both innate and adaptive immunity, understanding the impact of aging on Mφ function is important. In the past studies, we and others have shown that aging decreases Mφ responsiveness to classical activating signals (e.g. IFN-γ and lipopolysaccharide, LPS). In this study, we examined the impact of aging on Mφ signaling through the IFN-γ receptor pathway. Mφs from male Balb/c mice aged 2 (young) and 18-24 (old) months were purified and then stimulated with IFN-γ. Western blotting revealed a significant reduction (∼50%) in IFN-γ-stimulated tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT-1) α and β in Mφs from aged, when compared with young mice. This reduction in phospho-STAT-1 was associated with a significant constitutive reduction (∼80%) in total STAT-1α protein and a complete inhibition of STAT-1 gene expression in response to IFN-γ in old compared to young mice. These data may, in part, explain why classical Mφ responses like reactive nitrogen and oxygen species generation, tumor killing and microbicidal activity are lower in Mφs from aged subjects. We conclude that peritoneal Mφs from aged mice have an intrinsic defect in Jak-STAT signaling which prevents them from fully responding to IFN-γ.