data_sheet_1_Glucocorticoid-Induced Leucine Zipper Inhibits Interferon-Gamma Production in B Cells and Suppresses Colitis in Mice.PDF

Glucocorticoid-induced leucine zipper (GILZ) is transcriptionally upregulated by glucocorticoids (GCs) and mediates many of the anti-inflammatory effects of GCs. Since B cell activity has been linked to cytokine production and modulation of inflammatory responses, we herein investigated the role of GILZ in B cells during colitis development. B cell-specific gilz knock-out (gilz B cKO) mice exhibited increased production of the pro-inflammatory cytokine IFN-γ in B cells, and consequently CD4+ T cell activation. Increased IFN-γ production in B cells was associated with enhanced transcriptional activity of the transcription factor activator protein-1 (AP-1) on the IFN-γ promoter. Moreover, GILZ deficiency in B cells was linked to enhanced susceptibility to experimental colitis in mice, and this was reversed by administering GILZ protein. Interestingly, we observed increased production of IFN-γ in both B and T cells infiltrating the lamina propria (LP) of gilz B cKO mice. Together, these findings indicate that GILZ controls IFN-γ production in B cells, which also affects T cell activity, and increased production of IFN-γ by B and T cells in LP is associated with predisposition to inflammatory colitis in mice.

糖皮质激素诱导的亮氨酸拉链蛋白（GILZ）在糖皮质激素（GCs）的转录调控下表达上调，并介导了GCs的多种抗炎作用。鉴于B细胞活性与细胞因子产生以及对炎症反应的调节密切相关，本研究旨在探讨GILZ在结肠炎发展过程中B细胞中的作用。B细胞特异性gilz敲除（gilz B cKO）小鼠表现出B细胞中促炎细胞因子IFN-γ的产生增加，进而导致CD4+ T细胞的激活。B细胞中IFN-γ产生的增加与转录因子激活蛋白-1（AP-1）在IFN-γ启动子上的转录活性增强有关。此外，B细胞中GILZ的缺乏与小鼠实验性结肠炎的易感性增加有关，且通过给予GILZ蛋白可以逆转这一现象。有趣的是，我们在gilz B cKO小鼠的固有层（LP）浸润的B和T细胞中观察到IFN-γ的产生增加。综上所述，这些发现表明GILZ调控B细胞中的IFN-γ产生，这不仅影响T细胞活性，而且LP中B和T细胞IFN-γ的产生增加与小鼠易患炎症性结肠炎有关。