Molecular mechanisms underlying anti-inflammatory phenotype of neonatal splenic macrophages

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

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Neonatal humans and rodents are susceptible to infection with encapsulated bacteria as a result of an inability to make antibodies to capsular polysaccharides. This is partly a result of decreased production of proinflammatory cytokines by splenic macrophages (MΦ) from neonates. In this study, we show that when stimulated with a variety of agonists to TLR2, -4, and -9, neonatal MΦ make less proinflammatory cytokines and more IL-10 than adult MΦ. IL-10 appears to have a role in the decreased proinflammatory cytokine production, as neonatal MΦ treated with anti-IL-10 receptor antibody or from IL-10-/- mice produced levels of proinflammatory cytokines at a level comparable with that produced by adult MΦ. A microarray analysis of RNA from resting and LPS-stimulated MΦ from neonatal and adult mice showed that expression of a large number of genes encoding cytokines, chemokines, and their receptors was decreased dramatically in the neonatal MΦ, although some cytokines, including IL-10 and IL-16, were enhanced. Several genes in the TLR signaling pathway leading to NF-κB activation were down-regulated, which may account for the decreased chemokine and cytokine synthesis. It is surprising that p38α MAPK, known to be required for TLR-induced cytokine secretion, was enhanced in the neonatal MΦ. Our studies with the p38 MAPK inhibitor SB203580 suggested that excess p38 MAPK activity can be inhibitory for TLR2-, -4-, and -9-induced production of proinflammatory cytokines but not IL-10. The anti-inflammatory phenotype of the neonatal MΦ may be unique to the developing organism, although it compromises the neonate's ability to respond to encapsulated bacteria.

Original languageEnglish
Pages (from-to)403-416
Number of pages14
JournalJournal of Leukocyte Biology
Volume82
Issue number2
DOIs
StatePublished - Aug 1 2007

Keywords

  • CpG
  • Cytokines
  • LPS
  • Microarray
  • TLR
  • p38 MAPK

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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