RESUMO
Leprosy is a chronic human disease that results from infection of Mycobacterium leprae. T reg cells have been shown to have important implications in various diseases. However, in leprosy, it is still unclear whether T regs can mediate immune suppression during progression of the disease. In the present study, we have proposed the putative mechanism leading to high proportion of T reg cells and investigated its significance in human leprosy. High levels of TGF-ß followed by adaptation of FoxP3(+) naive and memory (CD4(+)CD45RA(+)/RO(+)) T cells were observed as the principal underlying factors leading to higher generation of T reg cells during disease progression. Furthermore, TGF-ß was found to be associated with increased phosphorylation-mediated-nuclear-import of SMAD3 and NFAT towards BL/LL pole to facilitate FoxP3 expression in these cells, the same as justified after using nuclear inhibitors of SMAD3 (SIS3) and NFAT (cyclosporin A) in CD4(+)CD25(+) cells in the presence of TGF-ß and IL-2. Interestingly, low ubiquitination of FoxP3 in T reg cells of BL/LL patients was revealed to be a major driving force in conferring stability to FoxP3 which in turn is linked to suppressive potential of T regs. The present study has also pinpointed the presence of CD4(+)CD25(+)IL-10(+) sub class of T regs (Tr1) in leprosy.
Assuntos
Fatores de Transcrição Forkhead/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Hanseníase/imunologia , Linfócitos T Reguladores/imunologia , Acetilação , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Adolescente , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Ciclosporina/farmacologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunossupressores/farmacologia , Interleucina-2/imunologia , Interleucina-2/metabolismo , Interleucina-2/farmacologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Isoquinolinas/farmacologia , Hanseníase/metabolismo , Hanseníase/patologia , Antígenos Comuns de Leucócito/imunologia , Antígenos Comuns de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Transcrição NFATC/antagonistas & inibidores , Fatores de Transcrição NFATC/imunologia , Fatores de Transcrição NFATC/metabolismo , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Pirróis/farmacologia , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/imunologia , Proteína Smad3/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Ubiquitinação , Adulto JovemRESUMO
The anti-leprosy agent, clofazimine, at concentrations of 0.1-5 micrograms/ml caused a dose-related, stimulus-non-specific (N-formyl-methionyl-leucyl-phenylalanine, calcium ionophore, opsonised zymosan, arachidonic acid and phorbol myristate acetate) potentiation of superoxide generation by human neutrophils in vitro without affecting basal oxidative responses. The pro-oxidative interactions of clofazimine with neutrophils were eliminated by the phospholipase A2 inhibitor 4-p-bromophenacyl bromide but not by the protein kinase C (PKC) inhibitor H-7. In support of these observations clofazimine promoted the release of radiolabeled arachidonic acid from neutrophil membrane phospholipids but did not influence the activity of PKC in cytosolic extracts of neutrophils or of purified PKC from rat brain. Pro-oxidative interactions of clofazimine with human phagocytes may contribute to the intraphagocytic antimycobacterial activity of this agent.