RESUMO
BACKGROUND AND AIMS: Persistent inflammation observed in inflammatory bowel disease may be the consequence of an increased or aberrant immune response to normal gut constituents or an overall immune dysregulation and imbalance. Cytokines play an important role in immune regulation and interleukin 18 (IL-18) is one such cytokine that has emerged as being instrumental in driving CD4+ T cell responses towards a Th1-type. IL-18 can also directly mediate inflammation, moderate interleukin 1 activity, and can act on cell types other than T cells. It has been reported recently that IL-18 mRNA and protein are upregulated in gut tissue from IBD patients. The aim of this study was to understand more about the role of IL-18 in contributing to the pathology of IBD and to assess whether blocking IL-18 activity may be of therapeutic benefit as a treatment regimen for IBD. METHODS: Mice with dextran sulphate sodium (DSS) induced colitis were treated with recombinant IL-18 binding protein (IL-18bp.Fc), a soluble protein that blocks IL-18 bioactivity. Histopathological analysis was performed and RNA from the large intestine was analysed using the RNase protection assay and gene arrays. RESULTS: IL-18 RNA levels increased very early in the colon during DSS colitis. Treatment of mice with IL-18bp.Fc inhibited IBD associated weight loss and significantly inhibited the intestinal inflammation induced by DSS. IL-18bp.Fc treatment also attenuated mRNA upregulation of multiple proinflammatory cytokine genes, chemokine genes, and matrix metalloprotease genes in the large intestine that are commonly elevated during IBD. CONCLUSIONS: IL-18bp treatment attenuated inflammation during DSS induced colitis in mice. Neutralising IL-18 activity may therefore be of benefit for ameliorating the inflammation associated with human intestinal diseases.
Assuntos
Colite Ulcerativa/induzido quimicamente , Sulfato de Dextrana/efeitos adversos , Glicoproteínas/farmacologia , Interleucina-18/antagonistas & inibidores , Animais , Colite Ulcerativa/patologia , Citocinas/metabolismo , Feminino , Imuno-Histoquímica/métodos , Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-18/fisiologia , Linfonodos/fisiologia , Mesentério , Camundongos , Camundongos Endogâmicos C57BL , RNA/metabolismo , Regulação para Cima , Redução de PesoRESUMO
Bacterial pneumonia is an increasing complication of HIV infection and inversely correlates with the CD4(+) lymphocyte count. Interleukin (IL)-17 is a cytokine produced principally by CD4(+) T cells, which induces granulopoiesis via granulocyte colony-stimulating factor (G-CSF) production and induces CXC chemokines. We hypothesized that IL-17 receptor (IL-17R) signaling is critical for G-CSF and CXC chemokine production and lung host defenses. To test this, we used a model of Klebsiella pneumoniae lung infection in mice genetically deficient in IL-17R or in mice overexpressing a soluble IL-17R. IL-17R-deficient mice were exquisitely sensitive to intranasal K. pneumoniae with 100% mortality after 48 h compared with only 40% mortality in controls. IL-17R knockout (KO) mice displayed a significant delay in neutrophil recruitment into the alveolar space, and had greater dissemination of K. pneumoniae compared with control mice. This defect was associated with a significant reduction in steady-state levels of G-CSF and macrophage inflammatory protein (MIP)-2 mRNA and protein in the lung in response to the K. pneumoniae challenge in IL-17R KO mice. Thus, IL-17R signaling is critical for optimal production of G-CSF and MIP-2 and local control of pulmonary K. pneumoniae infection. These data support impaired IL-17R signaling as a potential mechanism by which deficiency of CD4 lymphocytes predisposes to bacterial pneumonia.
Assuntos
Quimiocinas CXC/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Pulmão/metabolismo , Neutrófilos/citologia , Receptores de Interleucina/metabolismo , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Animais , Líquido da Lavagem Broncoalveolar , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina/genética , Receptores de Interleucina-17 , Proteínas Recombinantes/genéticaRESUMO
The elimination of lymphocytes within inflammatory lesions is a critical component in the resolution of disease once pathogens have been cleared. We report here that signaling through the TNF receptor p55 (TNFRp55) is required to eliminate lymphocytes from lesions associated with intracellular pathogens. Thus, TNFRp55-/- mice, but not Fas-deficient mice, maintained inflammatory lesions associated with either Leishmania major or Rhodococcus equi infection, although they developed a Th1 response and controlled the pathogens. Inflammatory cells from either L. major- or R. equi-infected C57BL/6 mice were sensitive to TNF-induced apoptosis, and conversely the number of apoptotic cells in the lesions from TNFRp55-/- mice was dramatically reduced compared with wild-type mice. Furthermore, in vivo depletion of TNF in wild-type mice blocked lesion regression following R. equi infection. Taken together, our results suggest that signaling through the TNFRp55, but not Fas, is required to induce apoptosis of T cells within inflammatory lesions once pathogens are eliminated, and that in its absence lesions fail to regress.
Assuntos
Antígenos CD/fisiologia , Leishmania major/patogenicidade , Receptores do Fator de Necrose Tumoral/fisiologia , Rhodococcus equi/patogenicidade , Infecções por Actinomycetales/etiologia , Infecções por Actinomycetales/imunologia , Infecções por Actinomycetales/patologia , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD/genética , Apoptose/imunologia , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/parasitologia , Líquido Intracelular/microbiologia , Líquido Intracelular/parasitologia , Leishmania major/imunologia , Leishmaniose Cutânea/etiologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Receptores do Fator de Necrose Tumoral/deficiência , Receptores do Fator de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral , Rhodococcus equi/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Receptor fas/fisiologiaRESUMO
TNF participates in the induction of nitric oxide (NO) production and macrophage activation, leading to the elimination of intracellular pathogens. We previously found that TNF receptor p55-deficient mice (TNFRp55-/-) control replication of Leishmania major in vivo but fail to resolve their lesions. Here we report that mice lacking the p75 receptor (TNFRp75-/-) or both receptors (TNFRp55p75-/-), also control parasite replication, albeit mice lacking the p55 receptor (either TNFRp55-/- or TNFRp55p75-/-) are delayed in their elimination of L. major compared with controls. All TNF receptor-deficient mice developed a Thl-type immune response and up-regulated inducible NO synthase (iNOS) mRNA gene expression in lesions during infection. Thus, neither TNF receptor appears to be absolutely required for NO production or elimination of L. major in vivo. In vitro, however, while macrophages from naive TNFRp75-/- mice could be activated to produce NO and kill L. major, we observed a defect in NO production and parasite killing by resident peritoneal macrophages from naive TNFRp55-/- or TNFRp55p75-/- mice. However, when macrophages were elicited with leishmanial Ag from 4-wk-infected TNFRp55-/- or TNFRp55p75-/- mice, they produced NO and were leishmanicidal. These data suggest that the TNFRp75 plays no essential role in L. major infection in mice and that the p55 receptor may be required for optimal macrophage activation. However, the results also show that a mechanism exists by which macrophages can be primed in vivo during L. major infection to produce NO and kill L. major in the absence of signaling through either of the TNF receptors.
Assuntos
Antígenos CD/metabolismo , Leishmania major/imunologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/prevenção & controle , Receptores do Fator de Necrose Tumoral/deficiência , Receptores do Fator de Necrose Tumoral/metabolismo , Animais , Antígenos CD/genética , Leishmania major/crescimento & desenvolvimento , Leishmaniose Cutânea/genética , Ativação de Macrófagos/genética , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , RNA Mensageiro/biossíntese , Receptores do Fator de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral , Receptores Tipo II do Fator de Necrose Tumoral , Células Th1/imunologia , Células Th1/metabolismo , Fatores de Tempo , Regulação para Cima/genética , Regulação para Cima/imunologiaAssuntos
Infecções por Clostridium/veterinária , Clostridium/classificação , Doenças dos Cavalos , Toxemia/veterinária , Animais , Toxinas Bacterianas , Clostridium/isolamento & purificação , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/patologia , Cavalos , Masculino , Orquiectomia , Toxemia/diagnóstico , Toxemia/patologiaRESUMO
Rhodococcal pneumonia is an important, life threatening disease of foals and immunosuppressed humans. Increased knowledge of the mechanisms of protective immunity are required in order to develop an effective immunoprophylaxis strategy for horses and immunotherapeutic regiments for people. Both humoral and cellular components of the immune system may be involved in immune clearance of R. equi. The susceptibility of foals less than 4-6 months of age is postulated to reflect waning maternal antibody, and passive transfer of hyperimmune plasma can provide protection on endemic farms. However, effective clearance is likely to require appropriate cellular responses, including the secretion of cytokines. In murine models, both CD4+ and CD8+ T lymphocytes can reduce bacterial counts in the lung. CD4+ cells appear to be both required and sufficient, and IFN-gamma is a primary mediator. Clearance appears to be a type 1 immune response while type 2 responses may lead to a failure to clear and lesion development. It remains to be determined how the cellular immunity experiments reported in mice relate to horses and humans. Likewise, the role of specific R. equi antigens in protective immunity has not been determined.
Assuntos
Infecções por Actinomycetales/veterinária , Doenças dos Cavalos , Rhodococcus equi , Infecções por Actinomycetales/imunologia , Infecções por Actinomycetales/prevenção & controle , Animais , Formação de Anticorpos , Suscetibilidade a Doenças , Feminino , Cavalos , Humanos , Imunidade Celular , Imunidade Materno-Adquirida , Camundongos , Gravidez , Rhodococcus equi/imunologiaRESUMO
Previous studies have associated the production of IL-10 with suppression of the protective cell-mediated immune response to Trypanosoma cruzi. To further understand the role of IL-10 in the resistance to and pathogenesis of Chagas' disease, we infected C57BL/6 wild-type (IL-10 +/+) or C57BL/6 IL-10 knockout (IL-10 -/-) mice with the virulent Tulahuen strain of T. cruzi. IL-10 -/- mice had a lower parasite burden and higher levels of serum TNF-alpha, IL-12, and IFN-gamma compared with infected IL-10 +/+ mice. However, infection resulted in earlier mortality of IL-10 -/- mice compared with IL-10 +/+ controls. The earlier mortality of IL-10 -/- mice could be reversed by administering rIL-10 or a neutralizing Ab specific for IL-12. A role for T cells in the early mortality of IL-10 -/- mice was suggested by experiments in which SCID IL-10 -/- mice infected with T. cruzi had a delay in time to death and significantly lower serum levels of IFN-gamma compared with IL-10 -/- mice. Furthermore, treatment of infected IL-10 -/- mice with a mAb specific for CD4 resulted in reduced serum levels of IFN-gamma and a delay in time to death. Altogether, our results demonstrate for the first time that during infection with T. cruzi there is a critical requirement for IL-10 to prevent the development of a pathologic immune response associated with CD4+ T cells and overproduction of IL-12.
Assuntos
Doença de Chagas/imunologia , Interleucina-10/fisiologia , Animais , Linfócitos T CD4-Positivos/imunologia , Doença de Chagas/mortalidade , Doença de Chagas/parasitologia , Interleucina-10/deficiência , Interleucina-10/genética , Interleucina-12/biossíntese , Interleucina-12/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Parasitemia/genética , Parasitemia/imunologia , Parasitemia/mortalidadeRESUMO
Rhodococcus equi, and intracellular respiratory pathogen, causes sever e granulomatous pneumonia in humans with AIDS and in young horses. Pulmonary clearance of R. equi requires functional CD4+ T cells and gamma interferon (IFN-gamma) expression from bronchial lymph node cells. The purpose of this study was to investigate whether R. equi-specific CD4+ Th1 cells could effect clearance of R. equi from the lung. Adoptive transfer of a clearance of R. equi from the lungs. In contrast, mice transfused with a R. equi-specific CD4+ Th2 cell line expressed interleukin-4 but not IFN-gamma mRNA, failed to clear pulmonary infection, and developed granulomas in the lung. Control mice, which did not receive cells, did not produce IFN-gamma or interleukin-4 and developed small pulmonary granulomas. These results clearly show that a Th1 response is sufficient to effect pulmonary clearance of R. equi.
Assuntos
Imunoterapia Adotiva , Pulmão/imunologia , Rhodococcus equi/imunologia , Células Th1/imunologia , Animais , Linhagem Celular , Citocinas/análise , Citocinas/genética , Feminino , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Mensageiro/análiseAssuntos
Doenças dos Bovinos/diagnóstico por imagem , Cistos/veterinária , Edema/veterinária , Doenças Testiculares/veterinária , Testículo/diagnóstico por imagem , Animais , Bovinos , Doenças dos Bovinos/patologia , Doenças dos Bovinos/cirurgia , Cistos/diagnóstico por imagem , Diagnóstico Diferencial , Edema/diagnóstico por imagem , Edema/patologia , Edema/cirurgia , Masculino , Orquiectomia/veterinária , Doenças Testiculares/diagnóstico por imagem , Doenças Testiculares/patologia , Doenças Testiculares/cirurgia , Testículo/patologia , UltrassonografiaRESUMO
Rhodococcus equi, a facultative intracellular bacterium, causes chronic, often fatal granulomatous pneumonia in young horses and in humans with AIDS. The inability of host alveolar macrophages to kill intracellular R. equi results in the development of granulomas and progressive loss of pulmonary parenchyma. Clearance of the organism from the lung requires functional CD4+ T cells. The purpose of this study was to identify the cytokine effector mechanisms that mediate clearance of R. equi from the lung. Mice were treated with monoclonal antibodies (MAbs) to either gamma interferon (IFN-gamma) or interleukin-4 (IL-4) to determine the role of endogenous production of these cytokines in pulmonary clearance of R. equi. Mice treated with an anti-IL-4 or isotype control MAb cleared R. equi by 21 days postinfection and expressed increased levels of IFN-gamma mRNA, as detected by transcriptional analysis of bronchial lymph node CD4+ T cells. In contrast, mice treated with the anti-IFN-gamma MAb failed to express detectable IFN-gamma mRNA, expressed increased levels of IL-4 mRNA, failed to clear pulmonary infection, and developed pulmonary granulomas with large numbers of eosinophils. The enhancement of IL-4 mRNA expression and a predominance of eosinophils in pulmonary lesions of anti-IFN-gamma-treated mice suggest that a nonprotective Th2 response in involved in disease pathogenesis. The association of increased bronchial lymph node CD4+ T-cell IFN-gamma mRNA expression with pulmonary clearance of R. equi suggests that a Th1 response is protective.
Assuntos
Infecções por Actinomycetales/imunologia , Interferon gama/fisiologia , Interleucina-4/fisiologia , Pulmão/imunologia , Pneumonia/microbiologia , Rhodococcus equi/imunologia , Animais , Feminino , Expressão Gênica , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/imunologia , RNA Mensageiro/genética , Células Th1/imunologia , Células Th2/imunologiaRESUMO
Pulmonary clearance of Rhodococcus equi requires functional T lymphocytes. In this study, CD8+ T-lymphocyte-deficient transgenic mice cleared virulent R. equi from the lungs while infection in CD4+ T-lymphocyte-deficient transgenic mice persisted. Although both CD4+ and CD8+ T cells function early in pulmonary defense against R. equi, clearance is dependent on CD4+ T lymphocytes.