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

Authors

Mosoka Papa Fallah, University of KentuckyFollow
R. Lakshman Chelvarajan, University of KentuckyFollow
Beth A. Garvy, University of KentuckyFollow
Subbarao Bondada, University of KentuckyFollow

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 TLR4 ligation. Here we showed that aged macrophages demonstrate similar cytokine dysregulation phenotype upon stimulation with TLR2 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.

Document Type

Article

Publication Date

6-2011

Notes/Citation Information

Published in Mechanisms of Ageing and Development, v. 132, issues 6-7, p. 274-286.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.

The document available for download is the author's post-peer-review final draft of the article.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.mad.2011.05.003

Funding Information

This study was supported by NIH grants to SB.

Related Content

Refer to Web version on PubMed Central for supplementary material.

Repository Citation

Fallah, Mosoka Papa; Chelvarajan, R. Lakshman; Garvy, Beth A.; and Bondada, Subbarao, "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" (2011). Microbiology, Immunology, and Molecular Genetics Faculty Publications. 126.
https://uknowledge.uky.edu/microbio_facpub/126