Molecular mechanisms underlying anti-inflammatory phenotype of neonatal splenic macrophages.
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 (MPhi) from neonates. In this study, we show that when stimulated with a variety of agonists to TLR2, -4, and -9, neonatal MPhi make less proinflammatory cytokines and more IL-10 than adult MPhi. IL-10 appears to have a role in the decreased proinflammatory cytokine production, as neonatal MPhi 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 MPhi. A microarray analysis of RNA from resting and LPS-stimulated MPhi 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 MPhi, although some cytokines, including IL-10 and IL-16, were enhanced. Several genes in the TLR signaling pathway leading to NF-kappaB activation were down-regulated, which may account for the decreased chemokine and cytokine synthesis. It is surprising that p38alpha MAPK, known to be required for TLR-induced cytokine secretion, was enhanced in the neonatal MPhi. 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 Mphi may be unique to the developing organism, although it compromises the neonate's ability to respond to encapsulated bacteria.
Chelvarajan
Lakshman
L
Sanders Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536, USA.
Popa
Diana
D
Liu
Yushu
Y
Getchell
Thomas V
TV
Stromberg
Arnold J
AJ
Bondada
Subbarao
S
D000375:Aging / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D019410:Interleukin-16 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D013154:Spleen / Q000166:cytology*; D051195:Toll-Like Receptor 2 / Q000819:agonists; D051197:Toll-Like Receptor 4 / Q000819:agonists; D051217:Toll-Like Receptor 9 / Q000819:agonists; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D019410:Interleukin-16; D008070:Lipopolysaccharides; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases