Burns Institute of Chinese PLA and Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Immunology. 2013 Oct;140(2):250-8. doi: 10.1111/imm.12135.
Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine and glucocorticoid (GC) counter-regulator, has emerged as an important modulator of inflammatory responses. However, the molecular mechanisms of MIF counter-regulation of GC still remain incomplete. In the present study, we investigated whether MIF mediated the counter-regulation of the anti-inflammatory effect of GC by affecting annexin 1 in RAW 264.7 macrophages. We found that stimulation of RAW 264.7 macrophages with lipopolysaccharide (LPS) resulted in down-regulation of annexin 1, while GC dexamethasone (Dex) or Dex plus LPS led to significant up-regulation of annexin 1 expression. RNA interference-mediated knockdown of intracellular MIF increased annexin 1 expression with or without incubation of Dex, whereas Dex-induced annexin 1 expression was counter-regulated by the exogenous application of recombinant MIF. Moreover, recombinant MIF counter-regulated, in a dose-dependent manner, inhibition of cytosolic phospholipase A2α (cPLA2α) activation and prostaglandin E2 (PGE2 ) and leukotriene B4 (LTB4 ) release by Dex in RAW 264.7 macrophages stimulated with LPS. Endogenous depletion of MIF enhanced the effects of Dex, reflected by further decease of cPLA2α expression and lower PGE2 and LTB4 release in RAW 264.7 macrophages. Based on these data, we suggest that MIF counter-regulates Dex-induced annexin 1 expression, further influencing the activation of cPLA2α and the release of eicosanoids. These findings will add new insights into the mechanisms of MIF counter-regulation of GC.
巨噬细胞移动抑制因子（MIF）是一种促炎细胞因子和糖皮质激素（GC）的反向调节剂，已成为炎症反应的重要调节剂。然而，MIF 对 GC 的反向调节的分子机制仍不完全清楚。在本研究中，我们研究了 MIF 是否通过影响 RAW 264.7 巨噬细胞中的膜联蛋白 1 来介导 GC 的抗炎作用的反向调节。我们发现，脂多糖（LPS）刺激 RAW 264.7 巨噬细胞导致膜联蛋白 1 的下调，而 GC 地塞米松（Dex）或 Dex 加 LPS 导致膜联蛋白 1 表达的显著上调。用 RNA 干扰介导的细胞内 MIF 敲低增加了 Dex 孵育前后的膜联蛋白 1 表达，而 Dex 诱导的膜联蛋白 1 表达则被外源性重组 MIF 的应用所反向调节。此外，重组 MIF 以剂量依赖的方式反向调节 LPS 刺激的 RAW 264.7 巨噬细胞中 Dex 诱导的细胞质磷脂酶 A2α（cPLA2α）激活和前列腺素 E2（PGE2）和白三烯 B4（LTB4）释放的抑制作用。内源性 MIF 的耗竭增强了 Dex 的作用，反映在 LPS 刺激的 RAW 264.7 巨噬细胞中 cPLA2α 表达的进一步降低以及 PGE2 和 LTB4 释放的降低。基于这些数据，我们认为 MIF 反向调节 Dex 诱导的膜联蛋白 1 表达，进一步影响 cPLA2α 的激活和前列腺素的释放。这些发现将为 MIF 对 GC 的反向调节机制提供新的见解。
