Haftmann Claudia, Stittrich Anna-Barbara, Zimmermann Jakob, Fang Zhuo, Hradilkova Kristyna, Bardua Markus, Westendorf Kerstin, Heinz Gitta A, Riedel René, Siede Julia, Lehmann Katrin, Weinberger Esther E, Zimmel David, Lauer Uta, Häupl Thomas, Sieper Joachim, Backhaus Marina, Neumann Christian, Hoffmann Ute, Porstner Martina, Chen Wei, Grün Joachim R, Baumgrass Ria, Matz Mareen, Löhning Max, Scheffold Alexander, Wittmann Jürgen, Chang Hyun-Dong, Rajewsky Nikolaus, Jäck Hans-Martin, Radbruch Andreas, Mashreghi Mir-Farzin
Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), an institute of the Leibniz AssociationBerlin, Berlin, Germany.
Eur J Immunol. 2015 Apr;45(4):1192-205. doi: 10.1002/eji.201444633. Epub 2015 Jan 22.
Repeatedly activated T helper 1 (Th1) cells present during chronic inflammation can efficiently adapt to the inflammatory milieu, for example, by expressing the transcription factor Twist1, which limits the immunopathology caused by Th1 cells. Here, we show that in repeatedly activated murine Th1 cells, Twist1 and T-bet induce expression of microRNA-148a (miR-148a). miR-148a regulates expression of the proapoptotic gene Bim, resulting in a decreased Bim/Bcl2 ratio. Inhibition of miR-148a by antagomirs in repeatedly activated Th1 cells increases the expression of Bim, leading to enhanced apoptosis. Knockdown of Bim expression by siRNA in miR-148a antagomir-treated cells restores viability of the Th1 cells, demonstrating that miR-148a controls survival by regulating Bim expression. Thus, Twist1 and T-bet not only control the differentiation and function of Th1 cells, but also their persistence in chronic inflammation.
在慢性炎症过程中反复激活的辅助性T细胞1（Th1细胞）能够有效地适应炎症环境，例如，通过表达转录因子Twist1来限制Th1细胞引起的免疫病理学效应。在此，我们表明，在反复激活的小鼠Th1细胞中，Twist1和T-bet可诱导微小RNA-148a（miR-148a）的表达。miR-148a调节促凋亡基因Bim的表达，导致Bim/Bcl2比值降低。在反复激活的Th1细胞中，用拮抗剂抑制miR-148a会增加Bim的表达，从而导致细胞凋亡增强。在miR-148a拮抗剂处理的细胞中，通过小干扰RNA（siRNA）敲低Bim表达可恢复Th1细胞的活力，这表明miR-148a通过调节Bim表达来控制细胞存活。因此，Twist1和T-bet不仅控制Th1细胞的分化和功能，还控制它们在慢性炎症中的持续存在。
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