RESUMO
The SLAM-associated protein (SAP) regulates IFN-gamma expression in leprosy. Tuberculoid leprosy patients locally produce Th1 cytokines, while lepromatous patients produce Th2 cytokines. Signaling lymphocytic activation molecule (SLAM) and the SLAM-associated protein (SAP) participate in the differentiation process that leads to the production of specific patterns of cytokines by activated T cells. To investigate the SLAM/SAP pathway in M. leprae infection, we determined the expression of SAP, IFN-gamma and SLAM RNA messenger in leprosy patients. We found a direct correlation of SLAM expression with IFN-gamma expression, whereas the expression of SAP was inversely correlated with the expression of both SLAM and IFN-gamma. Therefore, our data indicate that SAP might interfere with Th1 cytokine responses while SLAM expression may contribute to Th1 responses in leprosy. This study further suggests that the SLAM/SAP pathway might be a focal point for therapeutic modulation of T cell cytokine responses in diseases characterized by dysfunctional Th2 responses.
Assuntos
Glicoproteínas/biossíntese , Imunoglobulinas/biossíntese , Interferon gama/sangue , Hanseníase/imunologia , Células Th1/imunologia , Células Th2/imunologia , Antígenos CD , Estudos de Casos e Controles , Humanos , Hanseníase Tuberculoide/imunologia , RNA Mensageiro/sangue , Receptores de Superfície Celular , Membro 1 da Família de Moléculas de Sinalização da Ativação LinfocitáriaRESUMO
T cell production of IFN-gamma contributes to host defense against infection by intracellular pathogens, including mycobacteria. Lepromatous leprosy, the disseminated form of infection caused by Mycobacterium leprae, is characterized by loss of cellular response against the pathogen and diminished Th1 cytokine production. Relieving bacterial burden in Ag-unresponsive patients might be achieved through alternative receptors that stimulate IFN-gamma production. We have previously shown that ligation of signaling lymphocytic activation molecule (SLAM) enhances IFN-gamma in mycobacterial infection; therefore, we investigated molecular pathways leading from SLAM activation to IFN-gamma production in human leprosy. The expression of the SLAM-associated protein (an inhibitory factor for IFN-gamma induction) on M. leprae-stimulated cells from leprosy patients was inversely correlated to IFN-gamma production. However, SLAM ligation or exposure of cells from lepromatous patients to a proinflammatory microenvironment down-regulated SLAM-associated protein expression. Moreover, SLAM activation induced a sequence of signaling proteins, including activation of the NF-kappaB complex, phosphorylation of Stat1, and induction of T-bet expression, resulting in the promotion of IFN-gamma production, a pathway that remains quiescent in response to Ag in lepromatous patients. Therefore, our findings reveal a cascade of molecular events during signaling through SLAM in leprosy that cooperate to induce IFN-gamma production and strongly suggest that SLAM might be a focal point for therapeutic modulation of T cell cytokine responses in diseases characterized by dysfunctional Th2 responses.
Assuntos
Adjuvantes Imunológicos/fisiologia , Glicoproteínas/fisiologia , Imunoglobulinas/fisiologia , Líquido Intracelular/imunologia , Líquido Intracelular/microbiologia , Peptídeos e Proteínas de Sinalização Intracelular , Mycobacterium leprae/imunologia , Transdução de Sinais/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Adjuvantes Imunológicos/metabolismo , Antígenos CD , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/biossíntese , Células Cultivadas , Citocinas/fisiologia , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo/imunologia , Glicoproteínas/imunologia , Glicoproteínas/metabolismo , Humanos , Imunoglobulinas/imunologia , Imunoglobulinas/metabolismo , Líquido Intracelular/enzimologia , Líquido Intracelular/metabolismo , Hanseníase/enzimologia , Hanseníase/imunologia , Hanseníase/metabolismo , Ligantes , Ativação Linfocitária/imunologia , NF-kappa B/metabolismo , Transporte Proteico/imunologia , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-fyn , Receptores de Superfície Celular , Fator de Transcrição STAT1 , Índice de Gravidade de Doença , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária , Proteínas com Domínio T , Células Th1/enzimologia , Células Th1/microbiologia , Transativadores/metabolismo , Fatores de Transcrição/biossínteseRESUMO
La inmunidad protectora contra Mycobacterium leprae requiere IFN-gamma. Los pacientes con lepra tuberculoide producen localmente citoquinas Th1, mientras que los pacientes lepromatosos producen citoquinas Th2. La molécula linfocitaria activadora de señales (SLAM) y la proteína aociada a SLAM (SAP) participan en la diferenciación celular que conduce a producción de patrones específicos de citoquinas. A fin de investigar la vía SLAM/SAP en la infección por M. leprae, determinamos expresión de ARN mensajero (ARNm) de SAP, IFN-gamma y SLAM en pacientes con lepra. Obeservamos que la expresión de SLAM correlacionó en forma directa con la expresión de IFN-gamma, mientras que la expresión de SAP interferiría con las respuetas de citoquinas Th1 mientras que SLAM contribuiría con la respuesta Th1 en lepra, señalando a la vía SLAM/SAP como potencial blanco modulador de citoquinas en enfermedades con respuestas Th2 disfuncionales.
Assuntos
Humanos , Citocinas/biossíntese , Glicoproteínas/biossíntese , Interferon gama/sangue , Hanseníase/imunologia , Células Th1/imunologia , /imunologia , Estudos de Casos e Controles , RNA Mensageiro/sangueRESUMO
T cell production of IFN-gamma contributes to host defense against infections by intracellular pathogens, including mycobacteria. Lepromatous leprosy, the dissminated from of infection caused by Mycobacterium leprae, is characterized by loss of cellular response against the pathogen and diminished Th1 cytokine production. Relieving bacterial burden in Ag-unresponsive patients might be achieved through alternative receptors that stimulate IFN-gamma production. We have previously shown that ligation of signaling lymphocytic activation molecule (SLAM) enhances IFN-gamma in mycobacterial infection; therefore, we investigated molecular pathways leading from SLAM activation to IFN-gamma production in human leprosy. The expression of the SLAM-associated protein (an inhibitory factor for IFN-gamma induction) on M. leprae-stimulated cells from leprosy patients was inversely correlated to IFN-gamma production. Howevwe, SLAM ligation or exposure of cell from lepromatous patients to a proinflammatory microenvironment down-regulated SLAM-associated protein expression. Moreover. SALAM activation induced a sequence of signaling proteins, including activation of the NF-kB complex, phosphorylation of Stat1, and induction of T-bet expression, resulting in the promotion a cascade of molecular events during signaling through SLAM in leprosy that cooperate to induce INF-gamma production and strongly suggest that SLAM might be a focal point for therapeutic modulation of the cell cytokine responses in diseases characterized by dysfunctional Th2 responses
Assuntos
Humanos , Hanseníase/imunologia , Hanseníase/microbiologia , Interleucinas/imunologia , Interleucinas/sangue , Linfócitos T/imunologia , Linfócitos T/microbiologia , Linfócitos/imunologia , Linfócitos/microbiologia , Mycobacterium leprae/imunologia , Mycobacterium leprae/patogenicidadeRESUMO
La inmunidad protectora contra Mycobacterium leprae requiere IFN-gamma. Los pacientes con lepra tuberculoide producen localmente citoquinas Th1, mientras que los pacientes lepromatosos producen citoquinas Th2. La molécula linfocitaria activadora de señales (SLAM) y la proteína aociada a SLAM (SAP) participan en la diferenciación celular que conduce a producción de patrones específicos de citoquinas. A fin de investigar la vía SLAM/SAP en la infección por M. leprae, determinamos expresión de ARN mensajero (ARNm) de SAP, IFN-gamma y SLAM en pacientes con lepra. Obeservamos que la expresión de SLAM correlacionó en forma directa con la expresión de IFN-gamma, mientras que la expresión de SAP interferiría con las respuetas de citoquinas Th1 mientras que SLAM contribuiría con la respuesta Th1 en lepra, señalando a la vía SLAM/SAP como potencial blanco modulador de citoquinas en enfermedades con respuestas Th2 disfuncionales. (AU)
Assuntos
Humanos , RESEARCH SUPPORT, NON-U.S. GOVT , Hanseníase/imunologia , Interferon gama/sangue , Glicoproteínas/biossíntese , Citocinas/biossíntese , Células Th1/imunologia , Células Th2/imunologia , RNA Mensageiro/sangue , Estudos de Casos e ControlesRESUMO
The SLAM-associated protein (SAP) regulates IFN-gamma expression in leprosy. Tuberculoid leprosy patients locally produce Th1 cytokines, while lepromatous patients produce Th2 cytokines. Signaling lymphocytic activation molecule (SLAM) and the SLAM-associated protein (SAP) participate in the differentiation process that leads to the production of specific patterns of cytokines by activated T cells. To investigate the SLAM/SAP pathway in M. leprae infection, we determined the expression of SAP, IFN-gamma and SLAM RNA messenger in leprosy patients. We found a direct correlation of SLAM expression with IFN-gamma expression, whereas the expression of SAP was inversely correlated with the expression of both SLAM and IFN-gamma. Therefore, our data indicate that SAP might interfere with Th1 cytokine responses while SLAM expression may contribute to Th1 responses in leprosy. This study further suggests that the SLAM/SAP pathway might be a focal point for therapeutic modulation of T cell cytokine responses in diseases characterized by dysfunctional Th2 responses.