RESUMO
Glucocorticoids can inhibit inflammation by abrogating the activity of NF-κB, a family of transcription factors that regulates the production of proinflammatory cytokines. To understand the molecular mechanism of repression of NF-κB activity by glucocorticoids, we performed a high-throughput siRNA oligo screen to identify novel genes involved in this process. Here, we report that loss of p53, a tumor suppressor protein, impaired repression of NF-κB target gene transcription by glucocorticoids. Additionally, loss of p53 also impaired transcription of glucocorticoid receptor (GR) target genes, whereas upstream NF-κB and glucocorticoid receptor signaling cascades remained intact. We further demonstrate that p53 loss severely impaired glucocorticoid rescue of death in a mouse model of LPS shock. Our findings unveil a new role for p53 in the repression of NF-κB by glucocorticoids and suggest important implications for treatment of the proinflammatory microenvironments found in tumors with aberrant p53 activity.
Assuntos
NF-kappa B/metabolismo , Receptores de Glucocorticoides/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Dexametasona/farmacologia , Ensaios de Triagem em Larga Escala , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mapas de Interação de Proteínas , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Choque Séptico/induzido quimicamente , Choque Séptico/genética , Choque Séptico/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genéticaRESUMO
Mast cells are known to play a pivotal role in allergic diseases such as allergic rhinitis, asthma, and atopic dermatitis by releasing granules containing histamine, LTC4, and other preformed chemical mediators. Previous reports have demonstrated that IKK2 (also called IKKß), a central intracellular component of NF-κB activation pathways, plays a critical role in IgE-mediated degranulation of mast cells and anaphylaxis in mice. In this study, we show that protein levels of tumor suppressor p53 are up-regulated upon IgE-mediated activation in mast cells and lack of p53 results in enhanced responses in both early and late phase anaphylaxis. p53 inhibits not only the catalytic activity of IKK2 presumably through the modulation of glycosylation but also p65 (RelA)-mediated transactivation. Our findings are the first to demonstrate that p53 functions as a negative regulator in mast cells.