title: Toxoplasma gondii triggers myeloid differentiation factor 88-dependent IL-12 and chemokine ligand 2 (monocyte chemoattractant protein 1) responses using distinct parasite molecules and host receptors.
abstract: Toll-like receptors (TLR) that signal through the common adaptor molecule myeloid differentiation factor 88 (MyD88) are essential in proinflammatory cytokine responses to many microbial pathogens. In this study we report that Toxoplasma gondii triggers neutrophil IL-12 and chemokine ligand 2 (CCL2; monocyte chemoattractant protein 1) production in strict dependence upon functional MyD88. Nevertheless, the responses are distinct. Although we identify TLR2 as the receptor triggering CCL2 production, parasite-induced IL-12 release did not involve this TLR. The production of both IL-12 and CCL2 was increased after neutrophil activation with IFN-gamma. However, the synergistic effect of IFN-gamma on IL-12, but not CCL2, was dependent upon Stat1 signal transduction. Although IL-10 was a potent down-regulator of Toxoplasma-triggered neutrophil IL-12 release, the cytokine had no effect on parasite-induced CCL2 production. Soluble tachyzoite Ag fractionation demonstrated that CCL2- and IL-12 inducing activities are biochemically distinct. Importantly, Toxoplasma cyclophilin-18, a molecule previously shown to induce dendritic cell IL-12, was not involved in neutrophil IL-12 production. Our results show for the first time that T. gondii possesses multiple molecules triggering distinct MyD88-dependent signaling cascades, that these pathways are independently regulated, and that they lead to distinct profiles of cytokine production.
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14850, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Del Rio
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Butcher
authors.forename: Soumaya
authors.initials: S
authors.lastname: Bennouna
authors.forename: Sara
authors.initials: S
authors.lastname: Hieny
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Denkers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D018932:Chemokine CCL2; D021983:Cyclophilins / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D009504:Neutrophils / Q000502:physiology; D014176:Protein Biosynthesis; D011956:Receptors, Cell Surface / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014122:Toxoplasma / Q000276:immunology*; D015534:Trans-Activators / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D015534:Trans-Activators; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D021983:Cyclophilins