RESUMO
The molecular process underlying T cell anergy is incompletely understood. Deltex1 (DTX1) is a Notch target with unknown physiological function. Here we show that Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1 therefore represents a component downstream of calcium-NFAT signaling that regulates T cell anergy.
Assuntos
Anergia Clonal/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição NFATC/metabolismo , Linfócitos T/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antígenos de Diferenciação/imunologia , Antígenos de Diferenciação/metabolismo , Autoimunidade/imunologia , Proteínas de Ligação a DNA/imunologia , Proteína 2 de Resposta de Crescimento Precoce/imunologia , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Proteínas Imediatamente Precoces/imunologia , Proteínas Imediatamente Precoces/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-cbl/imunologia , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Linfócitos T/metabolismo , Ubiquitina-Proteína Ligases , Regulação para Cima/imunologiaRESUMO
Toona sinensis Roem (TS) leaf tea as a health food for the improvement of blood sugar and hypertension has been demonstrated. Thioacetamide (TAA), a hepatotoxin, causes the progression of liver fibrosis. In this study, we tested the effects of TS leaf on TAA-induced liver injury. TAA (200mg/kg Bwt/3 days, i.p.) treated rats were orally administrated with TS leaf extract (1g/kg Bwt/10 days) three times. After 30 days treatment, the morphological data showed that TS leaf extract given to TAA-treated rats had less liver fibrosis. The GOT/GPT, collagen 1 and collagen 3 mRNAs of livers in TAA-treated rats were elevated when compared to normal rats. The improvements of GOT/GPT, collagen 1 and collagen 3 mRNAs were shown in the TS leaf extract given to TAA-treated rats. TS leaf extract given to TAA-treated rats showed higher levels of cytochrome P450 (1A1, 2A and reductase) than those of TAA-treated rats. Compared to the TAA-treated group, TGFbeta1 mRNA (RT-PCR) was decreased with an increase of TGFbetaR1 protein (western blot) in the TS leaf extract given to TAA-treated rats. The decreased tendency of FGFR2 was found in the TS leaf extract given to TAA-treated rats. The result implies that TS leaf possesses beneficial effects on liver injury through increments of detoxification and the metabolic pathway.