RESUMO
Thalidomide is being successfully used for the treatment of erythema nodosum leprosum (ENL), among other disorders with inflammatory and immunological bases. Although the active molecules responsible for the diverse therapeutic activities of the drug and the sequence of reactions triggered inside the cells remain unclear, it was demonstrated that thalidomide (THAL) inhibits TNFalpha mRNA expression and protein production by stimulated monocytes and activated T lymphocytes. Patients treated with THAL experienced a reduction in serum TNFalpha levels and it diminished cytokine gene expression at the lesion site, with a concomitant abrogation of clinical symptoms. It has been reported that thalidomide as well as some its analogues decrease M. leprae-induced TNFalpha and IL-12 mRNA in vitro. THAL also reduced monocyte apoptosis in the cultures. The present data further support thalidomide's effects on TNFa synthesis and the growing need to search for new specific TNFalpha inhibitors (non-teratogenic compounds) that might be potentially used in clinical disorders such as leprosy.
Assuntos
Eritema Nodoso/tratamento farmacológico , Imunossupressores/uso terapêutico , Talidomida/uso terapêutico , Apoptose/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Citocinas/genética , Humanos , Imunossupressores/farmacologia , Interleucina-12/antagonistas & inibidores , Monócitos/efeitos dos fármacos , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/genética , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Talidomida/análogos & derivados , Talidomida/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genéticaRESUMO
The immunomodulatory properties of thalidomide are currently being exploited therapeutically in conditions as diverse as erythema nodosum leprosum, chronic graft-vs-host disease, rheumatoid arthritis, and sarcoidosis. The relevant mechanism of action of thalidomide in these diseases remains unclear. The important role recently ascribed to IL-12, a cytokine critical to the development of cellular immune responses, in the pathogenesis of several of these conditions led us to examine whether thalidomide affects the production of IL-12. Thalidomide potently suppressed the production of IL-12 from human PBMC and primary human monocytes in a concentration-dependent manner. Thalidomide-induced inhibition of IL-12 production was additive to that induced by suboptimal inhibiting doses of dexamethasone, and occurred by a mechanism independent of known endogenous inhibitors of IL-12 production. These results suggest that thalidomide may have therapeutic utility in a wide range of immunologic disorders that are characterized by inappropriate cellular immune responses.