Song E, Ouyang N, Hörbelt M, Antus B, Wang M, Exton M S
Department of Nephrology, Institute of Internal Medicine, University Hospital, Essen, Germany.
Cell Immunol. 2000 Aug 25;204(1):19-28. doi: 10.1006/cimm.2000.1687.
Activated macrophages regulate fibrogenesis by providing cytokines and growth factors that modulate the proliferation and collagen synthesis of fibroblasts. However, macrophages can be activated in a classical pathway induced by LPS or IFN-gamma and an alternative pathway induced by IL-4 or glucocorticoid. Differently activated macrophages display distinct biological features. To clarify the difference between these two subsets of macrophages in the regulatory mechanisms controlling fibrogenesis, human peripheral blood monocytes were used as the source of macrophages and cocultivation of differently activated macrophages and a fibroblast cell line, WI-38, was performed. Alternatively activated macrophages increased the proliferation index and collagen synthesis of cocultivated WI-38 cells in comparison to untreated monocytes, while classically activated macrophages markedly reduced collagen production of cocultivated WI-38 cells. Additionally, mRNA expression and protein production of TGF-beta(1), PDGF-AA, and PDGF-BB were elevated in alternatively activated macrophages in parallel to their profibrogenic effects. In contrast, expression and production of TNF-alpha, as well as MMP-7, were enhanced in classically activated macrophages. These findings suggested that alternatively activated macrophages enhance fibrogenesis of fibroblasts by providing profibrogenic factors, while classically activated macrophages inhibit fibrogenesis of fibroblasts by releasing antifibrogenic or fibrolytic factors.
活化的巨噬细胞通过提供调节成纤维细胞增殖和胶原蛋白合成的细胞因子和生长因子来调节纤维化形成。然而，巨噬细胞可通过由脂多糖（LPS）或干扰素-γ诱导的经典途径以及由白细胞介素-4或糖皮质激素诱导的替代途径被激活。不同激活状态的巨噬细胞表现出不同的生物学特性。为了阐明这两种巨噬细胞亚群在控制纤维化形成的调节机制上的差异，使用人外周血单核细胞作为巨噬细胞来源，并将不同激活状态的巨噬细胞与成纤维细胞系WI-38进行共培养。与未处理的单核细胞相比，替代激活的巨噬细胞增加了共培养的WI-38细胞的增殖指数和胶原蛋白合成，而经典激活的巨噬细胞则显著降低了共培养的WI-38细胞的胶原蛋白产生。此外，转化生长因子-β1（TGF-β1）、血小板衍生生长因子-AA（PDGF-AA）和血小板衍生生长因子-BB（PDGF-BB）的mRNA表达和蛋白产生在替代激活的巨噬细胞中与其促纤维化作用平行升高。相反，肿瘤坏死因子-α（TNF-α）以及基质金属蛋白酶-7（MMP-7）的表达和产生在经典激活的巨噬细胞中增强。这些发现表明，替代激活的巨噬细胞通过提供促纤维化因子增强成纤维细胞的纤维化形成，而经典激活的巨噬细胞通过释放抗纤维化或纤溶因子抑制成纤维细胞的纤维化形成。
