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Published online before print May 10, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0107071

Received for publication January 26, 2007.
Revised March 31, 2007.
Accepted for publication April 12, 2007.

Article

Molecular mechanisms underlying anti-inflammatory phenotype of neonatal splenic macrophages

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

*Sanders Brown Center on Aging and Departments of Microbiology, Immunology & Molecular Genetics, Statistics, and Physiology, University of Kentucky, Lexington, Kentucky, USA

^@ To whom correspondence should be addressed. E-mail: bondada{at}uky.edu.

	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 (M) from neonates. In this study, we show that when stimulated with a variety of agonists to TLR2, -4, and -9, neonatal M make less proinflammatory cytokines and more IL-10 than adult M. IL-10 appears to have a role in the decreased proinflammatory cytokine production, as neonatal M 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 M. A microarray analysis of RNA from resting and LPS-stimulated M 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 M, although some cytokines, including IL-10 and IL-16, were enhanced. Several genes in the TLR signaling pathway leading to NF-B activation were down-regulated, which may account for the decreased chemokine and cytokine synthesis. It is surprising that p38 MAPK, known to be required for TLR-induced cytokine secretion, was enhanced in the neonatal M. 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 M may be unique to the developing organism, although it compromises the neonate’s ability to respond to encapsulated bacteria.

Key Words: TLR • LPS • CpG • cytokines • p38 MAPK • microarray