A defective protein kinase C anchoring system underlying age-associated impairment in TNF-alpha production in rat...

The ability of macrophages to secrete cytokines is important in host responses to infections inflammatory stimuli, both of which are altered with aging. In this study, age-associated changes in the release of TNF-alpha from LPS-stimulated rat alveolar macrophages were determined and correlated with a decrease in the level of RACK1, the anchoring protein involved in protein kinase C translocation and activation. Macrophages from aged rats produced approximately 50% less TNF-alpha than those from young rats. This effect was observed independently from the concentration of LPS used and the time considered. The decrease observed was associated with a defective PKC translocation, due to a reduction in the expression of RACK1, whereas no differences were detected in the expression of LPS receptor (CD14) or total PKC isoforms (alpha and betaIotaIota) in old and young rats. Use of RACK1 antisense oligonucleotide reduced the ability of young macrophages to respond to LPS, further supporting the idea that a deficit in RACK1 contributes to the functional impairment in aged macrophages and that age-induced macrophage immunodeficiencies are associated with alteration in signal transduction pathways.