Kim Sunjung, Elkon Keith B, Ma Xiaojing
Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Immunity. 2004 Nov;21(5):643-53. doi: 10.1016/j.immuni.2004.09.009.
Phagocytosis of apoptotic cells usually results in an anti-inflammatory state with inhibition of proinflammatory cytokines such as IL-12. How apoptotic cell-derived signals regulate IL-12 gene expression is not understood. We demonstrate that cell-cell contact with apoptotic cells is sufficient to induce profound inhibition of IL-12 production by activated macrophages. Phosphatidylserine could mimic the inhibitory effect. The inhibition does not involve autocrine or paracrine actions of IL-10 and TGF-beta. We report the identification, purification, and cloning of a novel zinc finger nuclear factor, named GC binding protein (GC-BP), that is induced following phagocytosis of apoptotic cells by macrophages or by treatment with phosphatidylserine. GC-BP selectively inhibits IL-12 p35 gene transcription by binding to its promoter in vitro and in vivo, thus decreasing IL-12 production. Blocking GC-BP by RNA interference restores IL-12 p35 transcription and IL-12 p70 synthesis. Finally, GC-BP itself undergoes functionally significant tyrosine dephosphorylation in response to apoptotic cells.
凋亡细胞的吞噬作用通常会导致一种抗炎状态，抑制诸如白细胞介素-12（IL-12）等促炎细胞因子。凋亡细胞衍生的信号如何调节IL-12基因表达尚不清楚。我们证明，与凋亡细胞的细胞间接触足以诱导活化巨噬细胞对IL-12产生的显著抑制。磷脂酰丝氨酸可模拟这种抑制作用。这种抑制不涉及IL-10和转化生长因子-β（TGF-β）的自分泌或旁分泌作用。我们报告了一种新型锌指核因子的鉴定、纯化和克隆，该因子名为GC结合蛋白（GC-BP），在巨噬细胞吞噬凋亡细胞或用磷脂酰丝氨酸处理后被诱导产生。GC-BP在体外和体内通过与其启动子结合来选择性抑制IL-12 p35基因转录，从而减少IL-12的产生。通过RNA干扰阻断GC-BP可恢复IL-12 p35转录和IL-12 p70合成。最后，GC-BP自身响应凋亡细胞发生功能上显著的酪氨酸去磷酸化。
