Hoppstädter Jessica, Kessler Sonja M, Bruscoli Stefano, Huwer Hanno, Riccardi Carlo, Kiemer Alexandra K
Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany;
Section of Pharmacology, Department of Medicine, University of Perugia, 06100 Perugia, Italy; and.
J Immunol. 2015 Jun 15;194(12):6057-67. doi: 10.4049/jimmunol.1403207. Epub 2015 May 11.
Induction of glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a key role in their anti-inflammatory action. In activated macrophages, GILZ levels are downregulated via tristetraprolin-mediated GILZ mRNA destabilization. To assess the functional significance of GILZ downregulation, we generated myeloid-specific GILZ knockout (KO) mice. GILZ-deficient macrophages displayed a higher responsiveness toward LPS, as indicated by increased TNF-α and IL-1β expression. This effect was due to an activation of ERK, which was significantly amplified in GILZ KO cells. The LPS-induced activation of macrophages is attenuated upon pretreatment of macrophages with low-dose LPS, an effect termed endotoxin tolerance. In LPS-tolerant macrophages, GILZ mRNA was stabilized, whereas ERK activation was strongly decreased. In contrast, GILZ KO macrophages exhibited a strongly reduced desensitization. To explore the contribution of GILZ expression in macrophages to endotoxin tolerance in vivo, we treated GILZ KO mice with repeated i.p. injections of low-dose LPS followed by treatment with high-dose LPS. LPS pretreatment resulted in reduced proinflammatory mediator expression upon high-dose LPS treatment in serum and tissues. In contrast, cytokine induction was preserved in tolerized GILZ KO animals. In summary, our data suggest that GILZ is a key regulator of macrophage functions.
糖皮质激素诱导的亮氨酸拉链（GILZ）的诱导在其抗炎作用中起关键作用。在活化的巨噬细胞中，GILZ水平通过锌指蛋白介导的GILZ mRNA去稳定化而下调。为了评估GILZ下调的功能意义，我们构建了髓系特异性GILZ基因敲除（KO）小鼠。GILZ缺陷型巨噬细胞对脂多糖（LPS）表现出更高的反应性，表现为肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）表达增加。这种效应是由于细胞外信号调节激酶（ERK）的激活，在GILZ基因敲除细胞中这种激活显著增强。巨噬细胞用低剂量LPS预处理后，LPS诱导的巨噬细胞激活减弱，这种效应称为内毒素耐受。在内毒素耐受的巨噬细胞中，GILZ mRNA稳定，而ERK激活则显著降低。相反，GILZ基因敲除的巨噬细胞脱敏作用明显减弱。为了探讨巨噬细胞中GILZ表达对体内内毒素耐受的作用，我们给GILZ基因敲除小鼠腹腔内重复注射低剂量LPS，然后用高剂量LPS处理。LPS预处理导致高剂量LPS处理后血清和组织中促炎介质表达降低。相反，在耐受的GILZ基因敲除动物中细胞因子诱导得以保留。总之，我们的数据表明GILZ是巨噬细胞功能的关键调节因子。
