Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages

Abstract

Aged humans and rodents are susceptible to infection with Streptococcus pneumoniae bacteria as a result of an inability to make antibodies to capsular polysaccharides. This is partly a result of decreased production of proinflammatory cytokines and increased production of interleukin (IL)-10 by macrophages (Mphi) from aged mice. To understand the molecular basis of cytokine dysregulation in aged mouse Mphi, a microarray analysis was performed on RNA from resting and lipopolysaccharide (LPS)-stimulated Mphi from aged and control mice using the Affymetrix Mouse Genome 430 2.0 gene chip. Two-way ANOVA analysis demonstrated that at an overall P < 0.01 level, 853 genes were regulated by LPS (169 in only the young, 184 in only the aged, and 500 in both). Expression analysis of systematic explorer revealed that immune response (proinflammatory chemokines, cytokines, and their receptors) and signal transduction genes were specifically reduced in aged mouse Mphi. Accordingly, expression of Il1 and Il6 was reduced, and Il10 was increased, confirming our previous results. There was also decreased expression of interferon-gamma. Genes in the Toll-like receptor-signaling pathway leading to nuclear factor-kappaB activation were also down-regulated but IL-1 receptor-associated kinase 3, a negative regulator of this pathway, was increased in aged mice. An increase in expression of the gene for p38 mitogen-activated protein kinase (MAPK) was observed with a corresponding increase in protein expression and enzyme activity confirmed by Western blotting. Low doses of a p38 MAPK inhibitor (SB203580) enhanced proinflammatory cytokine production by Mphi and reduced IL-10 levels, indicating that increased p38 MAPK activity has a role in cytokine dysregulation in the aged mouse Mphi.

Recruitment of Memory B Cells to Lymph Nodes Remote from the Site of Immunization Requires an Inflammatory Stimulus

“…Hence, the use of local anti-inflammatory agents to control airway inflammation may help to dampen respiratory allergies by preventing the recruitment of memory B cells. More importantly, aging has been associated with impaired inflammatory responses and TLR function (36)(37)(38), and our findings indicate that this might lead to poor memory B cell recruitment in aged individuals responding to infection.…”

Systems biology of aging in four species

“…The first transcriptional profiles of aging were generated in a limited number of mouse tissues such as muscle [27] and brain [28]. Recently, transcriptional profiles of such diverse organs as adipose tissue [29], heart [30], liver [31••], and macrophages [32] have been studied. A recent study by Edwards et al used an empirical Bayes approach to identify 712 transcripts that are age-regulated in mouse muscle that were enriched for genes active in the p53 proapoptotic pathway in addition to genes encoding mitochondrial proteins involved in energy generation [33].…”

Aging of the Immune System as a Prognostic Factor for Human Longevity

“…Overall, their data suggest that different loci contributed to variation in immune responses at each age, consistent with the mutation accumulation model of senescence. In mice, following LPS challenge, it was found that 500 genes were activated in macrophages from young and old individuals, but more than 150 were activated only in the old or only in the young (12).…”