Department of Dermatology, University Medical Center and Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, and Center of Excellence in Dermatology, The State of Baden-Württemberg, Mannheim, Germany.
Immunobiology. 2011 Jan-Feb;216(1-2):164-72. doi: 10.1016/j.imbio.2010.06.003. Epub 2010 Jun 15.
Macrophages play a key role in inflammation, tissue regeneration and tolerance. Their differentiation is regulated by tissue cells derived CSF-1 (M-CSF). The ability of macrophages to use autocrine M-CSF to control their differentiation and function remained controversial. In this study we investigated the regulation of M-CSF production by Th1 and Th2 cytokines (IFN-γ and IL-4) and tolerogenic stimuli - glucocorticoid dexamethasone in primary human monocyte derived macrophages. We show that IFN-γ and IL-4 efficiently induce production of M-CSF while glucocorticoid inhibited it in a dose dependent manner. Since glucocorticoid inhibits production of inflammatory cytokines we tested whether this effect is a result of inhibited M-CSF production. We showed that exogenous M-CSF rescues the ability of glucocorticoid-treated macrophages to produce TNF and IL-6 in response to LPS. These data indicate that glucocorticoid-treated macrophages retain the ability to respond to M-CSF. Analyzing the mechanism of this responsiveness, we showed that dexamethasone up-regulates surface expression of M-CSF receptor - CSF-1R. We conclude that the ability of macrophages to produce M-CSF secures macrophage differentiation under Th1 and Th2 conditions if tissue cells are unable to supply enough M-CSF. Increased surface expression of CSF-1R in tolerogenic conditions guarantees response to minute amounts of exogenous M-CSF.
巨噬细胞在炎症、组织再生和耐受中发挥关键作用。它们的分化受组织细胞衍生的 CSF-1（M-CSF）调节。巨噬细胞利用自分泌 M-CSF 来控制其分化和功能的能力仍然存在争议。在这项研究中，我们研究了 Th1 和 Th2 细胞因子（IFN-γ 和 IL-4）和耐受刺激物——糖皮质激素地塞米松对原代人单核细胞来源的巨噬细胞中 M-CSF 产生的调节。我们表明，IFN-γ 和 IL-4 能够有效地诱导 M-CSF 的产生，而糖皮质激素则以剂量依赖的方式抑制其产生。由于糖皮质激素抑制炎症细胞因子的产生，我们测试了这种效应是否是由于 M-CSF 产生受到抑制所致。我们表明，外源性 M-CSF 挽救了糖皮质激素处理的巨噬细胞在 LPS 刺激下产生 TNF 和 IL-6 的能力。这些数据表明，糖皮质激素处理的巨噬细胞保留了对 M-CSF 作出反应的能力。分析这种反应性的机制，我们表明地塞米松上调了 M-CSF 受体 CSF-1R 的表面表达。我们得出结论，在 Th1 和 Th2 条件下，如果组织细胞无法提供足够的 M-CSF，巨噬细胞产生 M-CSF 的能力可确保巨噬细胞分化。在耐受条件下，CSF-1R 的表面表达增加，可保证对微量外源性 M-CSF 的反应。
