RESUMEN
The cAMP response element modulator (CREM)alpha is a widely expressed transcriptional repressor that is important for the termination of the T cell immune response and contributes to the abnormal T cell function in patients with systemic lupus erythematosus. We present evidence that APCs of Crem(-/-) mice express increased amounts of the costimulatory molecule CD86 and induce enhanced Ag-dependent and Ag-independent T cell proliferation. Similarly, human APCs in which CREMalpha was selectively suppressed expressed more CD86 on the surface membrane. CREMalpha was found to bind to the CD86 promoter and suppressed its activity. Transfer of APCs from Crem(-/-) mice into naive mice facilitated a significantly stronger contact dermatitis response compared with mice into which APCs from Crem(+/+) mice had been transferred. We conclude that CREMalpha is an important negative regulator of costimulation and APC-dependent T cell function both in vitro and in vivo.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Antígeno B7-2/inmunología , Modulador del Elemento de Respuesta al AMP Cíclico/inmunología , Regulación de la Expresión Génica/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Modulador del Elemento de Respuesta al AMP Cíclico/genética , Modulador del Elemento de Respuesta al AMP Cíclico/metabolismo , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/patología , Citometría de Flujo , Expresión Génica/inmunología , Humanos , Activación de Linfocitos/inmunología , Ratones , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/inmunologíaRESUMEN
Tumor necrosis factor alpha (TNFalpha) is a pleiotropic cytokine involved in apoptotic cell death, cellular proliferation, differentiation, inflammation, and tumorigenesis. In tumors it is secreted by tumor associated macrophages and can have both pro- and anti-tumorigenic effects. To identify genes regulated by TNFalpha, we performed a gene trap screen in the mammary carcinoma cell line MCF-7 and recovered 64 unique, TNFalpha-induced gene trap integration sites. Among these were the genes coding for the zinc finger protein ZC3H10 and for the transcription factor grainyhead-like 3 (GRHL3). In line with the dual effects of TNFalpha on tumorigenesis, we found that ZC3H10 inhibits anchorage independent growth in soft agar suggesting a tumor suppressor function, whereas GRHL3 strongly stimulated the migration of endothelial cells which is consistent with an angiogenic, pro-tumorigenic function.