RESUMO
The aryl hydrocarbon receptor (AhR) is part of a signaling system that is mainly triggered by xenobiotic agents. Increasing evidence suggests that AhR may regulate immunity to infections. To determine the role of AhR in the outcome of toxoplasmosis, we used AhR-/- and wild-type (WT) mice. Following an intraperitoneal infection with Toxoplasma gondii (T. gondii), AhR-/- mice succumbed significantly faster than WT mice and displayed greater liver damage as well as higher serum levels of tumor necrosis factor (TNF)-alpha, nitric oxide (NO), and IgE but lower IL-10 secretion. Interestingly, lower numbers of cysts were found in their brains. Increased mortality was associated with reduced expression of GATA-3, IL-10, and 5-LOX mRNA in spleen cells but higher expression of IFN-gamma mRNA. Additionally, peritoneal exudate cells from AhR-/- mice produced higher levels of IL-12 and IFN-gamma but lower TLR2 expression than WT mice. These findings suggest a role for AhR in limiting the inflammatory response during toxoplasmosis.
Assuntos
Receptores de Hidrocarboneto Arílico/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/imunologia , Animais , Antígenos de Protozoários/imunologia , Líquido Ascítico/metabolismo , Encéfalo/imunologia , Feminino , Citometria de Fluxo , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Imunidade Inata/imunologia , Endogamia , Interferon gama/biossíntese , Interferon gama/sangue , Interferon gama/genética , Interleucinas/biossíntese , Interleucinas/sangue , Lipoxinas/biossíntese , Lipoxinas/genética , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Hidrocarboneto Arílico/deficiência , Receptores de Hidrocarboneto Arílico/genética , Baço/imunologia , Toxoplasmose Animal/metabolismo , Toxoplasmose Animal/patologia , Fator de Necrose Tumoral alfa/sangueRESUMO
Macrophage migration inhibitory factor (MIF) exerts either a protective or a deleterious role in the immune response to different pathogens. We analyzed herein the role of MIF in the host control of toxoplasmosis using MIF(-/-) mice backcrossed to either the BALB/c or the C57BL/6 genetic backgrounds. Both, wild-type (WT) BALB/c and MIF(-/-) BALB/c mice were susceptible to infection with highly virulent RH as well as moderately virulent ME49 strains of T. gondii. MIF(-/-) mice, however, showed greater liver damage and more brain cysts, produced less proinflammatory cytokines, and succumbed significantly faster than WT mice. Bone marrow-derived dendritic cells (BMDCs) from MIF(-/-) mice produced less interleukin-1beta, interleukin-12, and tumor necrosis factor-alpha than WT BMDCs after stimulation with soluble Toxoplasma antigen (STAg). Similar observations were made in CD11c(+) low-density cells isolated from the spleens of MIF(-/-) mice challenged with STAg. MIF(-/-) C57BL/6 mice succumbed to ME49 infection faster than their WT counterparts. C57BL/6 mice that succumbed to infection with the ME49 strain produced less MIF than resistant BALB/c mice similarly infected. Interestingly, an analysis of brains from patients with cerebral toxoplasmosis showed low levels of MIF expression. Together, these findings demonstrate that MIF plays a critical role in mediating host resistance against T. gondii.