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

R. Lakshman Chelvarajan, Yushu Liu, Diana Popa, Marilyn L. Getchell, Thomas V. Getchell, Arnold J. Stromberg, Subbarao Bondada

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

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 (MΦ) from aged mice. To understand the molecular basis of cytokine dysregulation in aged mouse MΦ, a microarray analysis was performed on RNA from resting and lipopolysaccharide (LPS)-stimulated MΦ 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 MΦ. Accordingly, expression of Il1 and Il6 was reduced, and Il10 was increased, confirming our previous results. There was also decreased expression of interferon-γ. Genes in the Toll-like receptor-signaling pathway leading to nuclear factor-κB 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 MΦ and reduced IL-10 levels, indicating that increased p38 MAPK activity has a role in cytokine dysregulation in the aged mouse MΦ.

Original languageEnglish
Pages (from-to)1314-1327
Number of pages14
JournalJournal of Leukocyte Biology
Volume79
Issue number6
DOIs
StatePublished - Jun 2006

Keywords

  • Inflammation
  • Microarray
  • p38 MAPK

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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