Role of phosphoinositide 3-kinase-Akt signaling pathway in the age-related cytokine dysregulation in splenic macrophages stimulated via TLR-2 or TLR-4 receptors

Mosoka P. Fallah, R. Lakshman Chelvarajan, Beth A. Garvy, Subbarao Bondada

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Age-associated defects in both B-lymphocytes and macrophages in elderly result in a reduction in the efficacy of vaccines to many Gram positive bacteria like Streptococcus pneumoniae. Splenic macrophages from aged mice have been shown to have a defect in production of pro-inflammatory cytokines (IL-6, IL-12, IL-1β, TNF-α) but exhibit increased production of IL-10 upon TLR-4 ligation. Here we showed that aged macrophages demonstrate similar cytokine dysregulation phenotype upon stimulation with TLR-2 ligands, or killed S. pneumoniae. We hypothesized that an age-associated increase in activity of phosphatidyl inositol 3-kinase (PI3K)-Akt signaling pathway may be playing a causal role in the age-associated cytokine dysregulation. We found that gene expression of both the regulatory (p85β) and the catalytic (p110δ) subunits of Class IA PI3K is higher in aged than in young splenic macrophages. The age-associated increase in the activity of PI3K was also demonstrated by an upregulation of P-Akt and its downstream target, glycogen synthase kinase-3 (GSK-3). Inhibition of PI3K enhanced induction of pro-inflammatory cytokines, by TLR-2/TLR-1, TLR-2/TLR-6 and TLR-4 ligands as well as heat killed S. pneumoniae (HKSP). Therefore, targeting PI3-Kinase could rescue cytokine dysregulation in aged macrophages and enhance the relevant pro-inflammatory cytokines needed to support B-cell activation and differentiation.

Original languageEnglish
Pages (from-to)274-286
Number of pages13
JournalMechanisms of Ageing and Development
Volume132
Issue number6-7
DOIs
StatePublished - Jun 2011

Bibliographical note

Funding Information:
This study was supported by NIH grants to SB. We thank Dr. Kaplan for his critical comments on the manuscript, Dr. Maria Bruno for help with the RT-PCR.

Keywords

  • Aging
  • Macrophages
  • Phosphatidyl inosital 3-kinase (PI3K)
  • Streptococcus pneumoniae
  • Toll-Like receptors

ASJC Scopus subject areas

  • Aging
  • Developmental Biology

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