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1.
Proc Natl Acad Sci U S A ; 108(28): 11578-83, 2011 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-21709234

RESUMO

The generation of reactive oxygen species (ROS) is inherent to immune responses. ROS are crucially involved in host defense against pathogens by promoting bacterial killing, but also as signaling agents coordinating the production of cytokines. Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca(2+)-permeable channel gated via binding of ADP-ribose, a metabolite formed under conditions of cellular exposure to ROS. Here, we show that TRPM2-deficient mice are extremely susceptible to infection with Listeria monocytogenes (Lm), exhibiting an inefficient innate immune response. In a comparison with IFNγR-deficient mice, TRPM2(-/-) mice shared similar features of uncontrolled bacterial replication and reduced levels of inducible (i)NOS-expressing monocytes, but had intact IFNγ responsiveness. In contrast, we found that levels of cytokines IL-12 and IFNγ were diminished in TRPM2(-/-) mice following Lm infection, which correlated with their reduced innate activation. Moreover, TRPM2(-/-) mice displayed a higher degree of susceptibility than IL-12-unresponsive mice, and supplementation with recombinant IFNγ was sufficient to reverse the unrestrained bacterial growth and ultimately the lethal phenotype of Lm-infected TRPM2(-/-) mice. The severity of listeriosis we observed in TRPM2(-/-) mice has not been reported for any other ion channel. These findings establish an unsuspected role for ADP-ribose and ROS-mediated cation flux for innate immunity, opening up unique possibilities for immunomodulatory intervention through TRPM2.


Assuntos
Imunidade Inata/fisiologia , Listeria monocytogenes/imunologia , Canais de Cátion TRPM/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Citocinas/biossíntese , Feminino , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Interferon gama/farmacologia , Interleucina-12/deficiência , Interleucina-12/genética , Interleucina-12/imunologia , Subunidade beta 2 de Receptor de Interleucina-12/deficiência , Subunidade beta 2 de Receptor de Interleucina-12/genética , Subunidade beta 2 de Receptor de Interleucina-12/imunologia , Listeria monocytogenes/patogenicidade , Listeriose/imunologia , Listeriose/prevenção & controle , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Proteínas Recombinantes , Canais de Cátion TRPM/deficiência , Canais de Cátion TRPM/genética , Receptor de Interferon gama
2.
J Exp Med ; 207(2): 327-37, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20123961

RESUMO

Production of type I interferon (IFN; IFN-alphabeta) increases host susceptibility to Listeria monocytogenes, whereas type II IFN (IFN-gamma) activates macrophages to resist infection. We show that these opposing immunological effects of IFN-alphabeta and IFN-gamma occur because of cross talk between the respective signaling pathways. We found that cultured macrophages infected with L. monocytogenes were refractory to IFN-gamma treatment as a result of down-regulation of the IFN-gamma receptor (IFNGR). The soluble factor responsible for these effects was identified as host IFN-alphabeta. Accordingly, macrophages and dendritic cells (DCs) showed reduced IFNGR1 expression and reduced responsiveness to IFN-gamma during systemic infection of IFN-alphabeta-responsive mice. Furthermore, the increased resistance of mice lacking the IFN-alphabeta receptor (IFNAR(-/-)) to L. monocytogenes correlated with increased expression of IFN-gamma-dependent activation markers by macrophages and DCs and was reversed by depletion of IFN-gamma. Thus, IFN-alphabeta produced in response to bacterial infection and other stimuli antagonizes the host response to IFN-gamma by down-regulating the IFNGR. Such cross talk permits prioritization of IFN-alphabeta-type immune responses and may contribute to the beneficial effects of IFN-beta in treatment of inflammatory diseases such as multiple sclerosis.


Assuntos
Interferon Tipo I/metabolismo , Interferon gama/metabolismo , Listeria monocytogenes , Listeriose/imunologia , Ativação de Macrófagos , Macrófagos/imunologia , Macrófagos/microbiologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Regulação para Baixo , Feminino , Imunidade Inata , Interferon Tipo I/imunologia , Interferon gama/imunologia , Interferon gama/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Receptores de Interferon/antagonistas & inibidores , Receptores de Interferon/metabolismo , Receptor de Interferon gama
3.
J Immunol ; 178(4): 2407-14, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17277147

RESUMO

Both peptidoglycan and muropeptides potently modulate inflammatory and innate immune responses. The secreted Listeria monocytogenes p60 autolysin digests peptidoglycan and promotes bacterial infection in vivo. Here, we report that p60 contributes to bacterial subversion of NK cell activation and innate IFN-gamma production. L. monocytogenes deficient for p60 (Deltap60) competed well for expansion in mice doubly deficient for IFNAR1 and IFN-gammaR1 or singly deficient for IFN-gammaR1, but not in wild-type, IFNAR1(-/-), or TLR2(-/-) mice. The restored competitiveness of p60-deficient bacteria suggested a specific role for p60 in bacterial subversion of IFN-gamma-mediated immune responses, since in vivo expansion of three other mutant L. monocytogenes strains (DeltaActA, DeltaNamA, and DeltaPlcB) was not complemented in IFN-gammaR1(-/-) mice. Bacterial expression of p60 was not required to induce socs1, socs3, and il10 expression in infected mouse bone marrow macrophages but did correlate with enhanced production of IL-6, IL-12p70, and most strikingly IFN-gamma. The primary source of p60-dependent innate IFN-gamma was NK cells, whereas bacterial p60 expression did not significantly alter innate IFN-gamma production by T cells. The mechanism for p60-dependent NK cell stimulation was also indirect, given that treatment with purified p60 protein failed to directly activate NK cells for IFN-gamma production. These data suggest that p60 may act on infected cells to indirectly enhance NK cell activation and increase innate IFN-gamma production, which presumably promotes early bacterial expansion through its immunoregulatory effects on bystander cells. Thus, the simultaneous induction of IFN-gamma production and factors that inhibit IFN-gamma signaling may be a common strategy for misdirection of early antibacterial immunity.


Assuntos
Proteínas de Bactérias/imunologia , Interferon gama/imunologia , Células Matadoras Naturais/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Ativação Linfocitária/imunologia , N-Acetil-Muramil-L-Alanina Amidase/imunologia , Animais , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/genética , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/microbiologia , Efeito Espectador/imunologia , Regulação Bacteriana da Expressão Gênica/imunologia , Imunidade Inata/genética , Interferon gama/biossíntese , Interleucina-12/biossíntese , Interleucina-12/imunologia , Interleucina-6/biossíntese , Interleucina-6/imunologia , Células Matadoras Naturais/metabolismo , Listeria monocytogenes/genética , Listeria monocytogenes/metabolismo , Listeria monocytogenes/patogenicidade , Listeriose/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mutação , N-Acetil-Muramil-L-Alanina Amidase/biossíntese , N-Acetil-Muramil-L-Alanina Amidase/genética , Receptores de Interferon/deficiência , Receptores de Interferon/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
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