Toxoplasma gondii inhibits covalent modification of histone H3 at the IL-10 promoter in infected macrophages.
Infection of macrophages with the protozoan parasite Toxoplasma gondii results in inhibition of a large panel of LPS-responsive cytokines, including TNF-alpha, while leaving others such as IL-10 intact. Recent studies provide evidence that the parasite interferes with chromatin remodeling at the TNF-alpha promoter that is normally associated with LPS stimulation, but that is not required for TLR4 induction of IL-10. Here, we examined the effect of Toxoplasma on IL-10 induced by simultaneous signaling through TLR4 and FcgammaR, a combined stimulus that triggers histone H3 covalent modification at the IL-10 promoter resulting in high level IL-10 cytokine production. We show that the parasite inhibits high level IL-10 production and prevents histone H3 Ser(10) phosphorylation and Lys(9/14) acetylation at the IL-10 promoter. These results provide compelling evidence that T. gondii targets the host cell chromatin remodeling machinery to down-regulate cytokine responses in infected macrophages.
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
Jin
J
Leng
Eric Y
EY
Denkers
D000818:Animals; D001854:Bone Marrow Cells / Q000469:parasitology; D005347:Fibroblasts / Q000378:metabolism / Q000469:parasitology; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017452:Receptors, IgG / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014122:Toxoplasma / Q000378:metabolism*
D006657:Histones; D008070:Lipopolysaccharides; D017452:Receptors, IgG; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D012694:Serine