RESUMEN
A subset of CD4 + lymphocytes, regulatory T cells (Tregs), are necessary for central tolerance and function as suppressors of autoimmunity against self-antigens. The SRC-3 coactivator is an oncogene in multiple cancers and is capable of potentiating numerous transcription factors in a wide variety of cell types. Src-3 knockout mice display broad lymphoproliferation and hypersensitivity to systemic inflammation. Using publicly available bioinformatics data and directed cellular approaches, we show that SRC-3 also is highly enriched in Tregs in mice and humans. Human Tregs lose phenotypic characteristics when SRC-3 is depleted or pharmacologically inhibited, including failure of induction from resting T cells and loss of the ability to suppress proliferation of stimulated T cells. These data support a model for SRC-3 as a coactivator that actively participates in protection from autoimmunity and may support immune evasion of cancers by contributing to the biology of Tregs.
Asunto(s)
Proliferación Celular , Coactivador 3 de Receptor Nuclear/inmunología , Linfocitos T Reguladores/inmunología , Animales , Humanos , Ratones , Ratones Noqueados , Coactivador 3 de Receptor Nuclear/genéticaRESUMEN
Natural killer (NK)-cell development and maturation is a well-organized process. The steroid receptor coactivator 3 (SRC-3) is a regulator of the hematopoietic and immune systems; however, its role in NK cells is poorly understood. Here, SRC-3 displayed increased nuclear translocation in NK cells during terminal differentiation and upon inflammatory cytokine stimulation. Targeted deletion of SRC-3 altered normal NK-cell distribution and compromised NK-cell maturation. SRC-3 deficiency led to significantly impaired NK-cell functions, especially their antitumor activity. The expression of several critical T-bet target genes, including Zeb2, Prdm1, and S1pr5, but not T-bet itself, was markedly decreased in NK cells in the absence of SRC-3. There was a physiologic interaction between SRC-3 and T-bet proteins, where SRC-3 was recruited by T-bet to regulate the transcription of the aforementioned genes. Collectively, our findings unmask a previously unrecognized role of SRC-3 as a coactivator of T-bet in NK-cell biology and indicate that targeting SRC-3 may be a promising strategy to increase the tumor surveillance function of NK cells.
Asunto(s)
Células Asesinas Naturales/inmunología , Coactivador 3 de Receptor Nuclear/inmunología , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Coactivador 3 de Receptor Nuclear/deficienciaRESUMEN
Steroid receptor coactivator-3 (SRC-3) is a multifunctional protein that plays an important role in mammary gland growth, development, and tumorigenesis. In this study, SCR-3 gene knockout mice were used to study the effects of SCR-3 on the immunosuppression accompanied with systemic inflammatory response syndrome (SIRS). Bacterial clearance assay was performed by blood culture and frozen sections, and the results showed that the absence of SCR-3 protein serious damaged the innate immune system and the body's ability to inactivate or phagocytosis of bacteria was significantly decreased, and the absence of SCR-3 protein also weakened phagocytes' ability to degrade bacteria and their metabolites. Furthermore, animal model of inflammatory reaction was established and the immune function was determined, and the results revealed that SRC-3 protein may play an important role in maintenance of T-cells' immune function, and severe T-cell immune function disorder would be resulted once SRC-3 protein is missing. In addition, the results of our study showed the steady-state of lymphocyte subsets was destroyed after SIRS, leading the suppression of cellular immune function, and the absence of SCR-3 protein may aggravate the suppression of T-lymphocyte function. Therefore, the present study demonstrated that the absence of SCR-3 protein would aggravate immunosuppression. In addition, SRC-3 protein is a significant regulator of infection and inflammation, and SRC-3 protein play an essential role in the development of immunosuppression accompanied with SIRS.
Asunto(s)
Inmunidad Innata , Coactivador 3 de Receptor Nuclear/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Linfocitos T/inmunología , Animales , Bacterias/patogenicidad , Femenino , Inmunidad Innata/genética , Interleucina-2/sangre , Lipopolisacáridos/administración & dosificación , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/inmunología , Ratones , Ratones Noqueados , Coactivador 3 de Receptor Nuclear/deficiencia , Coactivador 3 de Receptor Nuclear/genética , Fagocitosis/genética , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/genética , Linfocitos T/patologíaRESUMEN
Steroid receptor coactivator 3 (SRC-3) is a multifunctional protein that plays an important role in regulation of bacterial LPS-induced inflammation. However, its involvement in host defense against bacterial infection remains unclear. In this study, we used SRC-3 knockout mice to assess the role of SRC-3 in antibacterial defense in Escherichia coli-induced septic peritonitis. After E. coli bacteria were injected i.p., SRC-3-deficient mice exhibited excessive local and systemic inflammatory responses and more severe bacterial burdens, leading to a significantly higher mortality compared with wild-type mice. Peritoneal macrophages of SRC-3-deficient mice showed a decrease in bacterial phagocytosis in culture and an increase in apoptosis, which was consistent with the defective bacterial clearance observed in SRC-3-deficient mice. Accordingly, SRC-3 null macrophages expressed much lower levels of scavenger receptor A, the antioxidant enzyme catalase, and antiapoptotic gene Bcl-2. Collectively, our data demonstrate that SRC-3 is important not only in modulating the local and systemic inflammation but also in intensifying bacterial clearance, which highlights a pivotal role of SRC-3 in the host defense system against bacterial infection.
Asunto(s)
Infecciones por Escherichia coli/inmunología , Inflamación/inmunología , Coactivador 3 de Receptor Nuclear/inmunología , Peritonitis/inmunología , Sepsis/inmunología , Animales , Apoptosis/inmunología , Inmunoprecipitación de Cromatina , Citocinas/biosíntesis , Citocinas/inmunología , Infecciones por Escherichia coli/genética , Inflamación/genética , Macrófagos Peritoneales/inmunología , Ratones , Ratones Noqueados , Coactivador 3 de Receptor Nuclear/genética , Peritonitis/genética , Fagocitosis/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sepsis/genética , TransfecciónRESUMEN
OBJECTIVE: To cross-link the McAb 1A2E1 to BNHS reagents and apply this biotinylated McAb to detect AIB1 antigen of target cells. METHODS: The McAb 1A2E1 was mixed with BNHS reagents to generate Biotin-1A2E1. The competitive inhibition ELISA and immunocytochemical method were applied to detect the biologic activity of antibody. RESULTS: The antibody kept high biological activities (with a titer of 1 : 3200) and sensitivities in detecting the AIB1 protein of breast cancer cell. CONCLUSION: The method of preparing biotinylated McAb is successful, and the prepared biotinylated McAb can be applied to detect target cells which express AIB1 antigen. This McAb provide useful tool for tumor auxiliary diagnosis.