RESUMEN
The thiol-disulfide oxidoreductase thioredoxin-1 (Trx1) is known to be secreted by leukocytes and to exhibit cytokine-like properties. Extracellular effects of Trx1 require a functional active site, suggesting a redox-based mechanism of action. However, specific cell surface proteins and pathways coupling extracellular Trx1 redox activity to cellular responses have not been identified so far. Using a mechanism-based kinetic trapping technique to identify disulfide exchange interactions on the intact surface of living lymphocytes, we found that Trx1 catalytically interacts with a single principal target protein. This target protein was identified as the tumor necrosis factor receptor superfamily member 8 (TNFRSF8/CD30). We demonstrate that the redox interaction is highly specific for both Trx1 and CD30 and that the redox state of CD30 determines its ability to engage the cognate ligand and transduce signals. Furthermore, we confirm that Trx1 affects CD30-dependent changes in lymphocyte effector function. Thus, we conclude that receptor-ligand signaling interactions can be selectively regulated by an extracellular redox catalyst.
Asunto(s)
Antígeno Ki-1/metabolismo , Transducción de Señal , Tiorredoxinas/metabolismo , Anticuerpos/inmunología , Catálisis , Línea Celular , Membrana Celular/metabolismo , Disulfuros/metabolismo , Epítopos/inmunología , Humanos , Antígeno Ki-1/agonistas , Antígeno Ki-1/clasificación , Antígeno Ki-1/inmunología , Cinética , Ligandos , Linfocitos/metabolismo , Oxidación-Reducción , Unión Proteica , Sensibilidad y Especificidad , Transducción de Señal/efectos de los fármacos , Tiorredoxinas/genéticaRESUMEN
CD30 expression is found on Hodgkin and Reed-Sternberg cells, anaplastic large cell lymphoma cells and on activated B or T lymphocytes. Recently CD30 was shown to be a transmembrane receptor that is significantly homologous to the tumor necrosis factor receptor (TNFR) family. Ligands for most members of this family, including CD30, have now been identified. This review summarizes the role of the different TNFR family members in lymphocyte proliferation and differentiation in an attempt to understand more clearly the role of CD30 expression in the pathogenesis and clinical behavior of non-Hodgkin's lymphomas. We state that CD30 expression is of prognostic relevance in primary cutaneous and nodal T cell lymphomas in contrast to the absence of clinical relevance of CD30 expression in B cell lymphomas.