title: Regulatory actions of Toll-like receptor 2 (TLR2) and TLR4 in Leishmania donovani infection in the liver.
abstract: In livers of susceptible but self-curing C57BL/6 mice, intracellular Leishmania donovani infection enhanced Toll-like receptor 4 (TLR4) and TLR2 gene expression. In the liver, infected TLR4(-/-) mice showed reduced gamma interferon (IFN-γ), tumor necrosis factor (TNF), and inducible nitric oxide synthase (iNOS) mRNA expression, higher-level and slowly resolving infection, delayed granuloma formation, and little response to low-dose chemotherapy; in serum, the ratio of IFN-γ to interleukin 10 (IL-10) activity was decreased by 50%. In contrast, in TLR2(-/-) mice, control of liver infection, parasite killing, and granuloma assembly were accelerated and chemotherapy's efficacy enhanced. In livers of infected TLR2(-/-) mice, mRNA expression was not increased for inflammatory cytokines or iNOS or decreased for IL-10; however, the serum IFN-γ/IL-10 ratio was increased 6.5-fold and minimal responses to IL-10 receptor blockade suggested downregulated IL-10. In established infection in wild-type mice, blockading TLR2 induced parasite killing and triggering TLR4 strengthened resistance and promoted chemotherapy's effect. Thus, in experimental L. donovani infection in the liver, TLR4 signaling upregulates and TLR2 signaling downregulates macrophage antileishmanial activity, making both receptors potential therapeutic targets in visceral leishmaniasis for engagement (TLR4) or blockade (TLR2).
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, USA. hwmurray@med.cornell.edu
authors.forename: Henry W
authors.initials: HW
authors.lastname: Murray
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Vanitha S
authors.initials: VS
authors.lastname: Raman
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Ma
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000276:immunology*; D055666:Lipopeptides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000469:parasitology*; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
chemical_list: D000981:Antiprotozoal Agents; C556062:IL10 protein, mouse; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II