RESUMEN
FcepsilonRI expression and function is a central aspect of allergic disease. Using bone marrow-derived mouse mast cell populations, we have previously shown that the Th2 cytokine IL-4 inhibits FcepsilonRI expression and function. In the current study we show that the Th2 cytokine IL-10 has similar regulatory properties, and that it augments the inhibitory effects of IL-4. FcepsilonRI down-regulation was functionally significant, as it diminished inflammatory cytokine production and IgE-mediated FcepsilonRI up-regulation. IL-10 and IL-4 reduced FcepsilonRI beta protein expression without altering the alpha or gamma subunits. The ability of IL-4 and IL-10 to alter FcepsilonRI expression by targeting the beta-chain, a critical receptor subunit known to modulate receptor expression and signaling, suggests the presence of a Th2 cytokine-mediated homeostatic network that could serve to both initiate and limit mast cell effector function.
Asunto(s)
Regulación hacia Abajo/inmunología , Interleucina-10/fisiología , Mastocitos/inmunología , Mastocitos/metabolismo , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/biosíntesis , Receptores de IgE/antagonistas & inhibidores , Receptores de IgE/biosíntesis , Adyuvantes Inmunológicos/farmacología , Animales , Células Cultivadas , Regulación hacia Abajo/genética , Sinergismo Farmacológico , Inmunoglobulina E/fisiología , Interleucina-4/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Subunidades de Proteína/genética , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/biosíntesis , Receptores de IgE/genética , Factor de Transcripción STAT6 , Transactivadores/deficiencia , Transactivadores/genética , Transactivadores/fisiología , Regulación hacia Arriba/inmunologíaRESUMEN
Interleukin-3 (IL-3) and stem cell factor (SCF) are important mast cell growth and differentiation factors. Since both cytokines activate the transcription factor signal transducer and activator of transcription 5 (Stat5), a known regulator of proliferation and survival, we investigated the effects of Stat5 deficiency on mast cell development and survival. Bone marrow-derived mast cell (BMMC) populations cultured from Stat5A/B-deficient mice survived in IL-3 + SCF, but not in either cytokine alone. These cells demonstrated reduced expression of Bcl-2, Bcl-x(L), cyclin A2, and cyclin B1, with increased apoptosis and delayed cell cycle progression during IL-3 or SCF culture. Finally, the absence of Stat5 resulted in loss of in vivo mast cell development, as judged by assessments of Stat5-deficient mice and transplantation of Stat5-deficient bone marrow cells to mast cell-deficient recipient mice. These results indicate that Stat5A and Stat5B are critical regulators of in vitro and in vivo mast cell development and survival.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Mastocitos/citología , Proteínas de la Leche , Transactivadores/fisiología , Animales , Caspasas/metabolismo , Células Cultivadas , Ciclinas/biosíntesis , Ciclinas/genética , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/deficiencia , Activación Enzimática/genética , Humanos , Interleucina-3/farmacología , Mastocitos/fisiología , Ratones , Ratones Endogámicos C57BL , Mitocondrias/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Proteínas Recombinantes/farmacología , Factor de Transcripción STAT5 , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factor de Células Madre/farmacología , Transactivadores/biosíntesis , Transactivadores/deficiencia , Proteínas Supresoras de Tumor , Regulación hacia ArribaRESUMEN
Interleukin-3 (IL-3) and stem cell factor (SCF) are important mast cell growth and differentiation factors. Since both cytokines activate the transcription factor Stat5, a known regulator of proliferation and survival, we investigated the effects of Stat5 deficiency on mast cell development and survival. This article will review data presented at The Fourth International Workshop on Signal Transduction in the Activation and Development of Mast Cells and Basophils. The full set of data is now in preparation for publication. We find that the absence of Stat5 A and B results in a total loss of in vivo mast cell development. Bone marrow-derived mast cell (BMMC) populations can be cultured and maintained from Stat5-deficient mice in IL-3+SCF, but not in either cytokine alone. The absence of Stat5 resulted in aberrant control of Bcl-2, Bcl-x(L) and cyclin A2, with increased apoptosis and delayed cell cycle progression after IL-3 or SCF stimulation. These results indicate that Stat5 A and B are critical regulators of in vitro and in vivo mast cell biology.
