Kodelja V, Müller C, Tenorio S, Schebesch C, Orfanos C E, Goerdt S
Klinik und Poliklinik für Dermatologie, Universitätsklinikum Bejamin Franklin, Freie Universität Berlin, Germany.
Immunobiology. 1997 Nov;197(5):478-93. doi: 10.1016/S0171-2985(97)80080-0.
Macrophages (M phi) are important for angiogenesis during inflammation, wound repair, and tumor growth. However, well-characterized M phi subsets such as IFN-gamma-induced, classically activated (ca) M phi or IL-4/glucocorticoid-induced, alternatively activated (aa) M phi have not been thoroughly examined for a positive or negative association with angiogenesis. While caM phi populate early inflammatory reactions and high-turnover granulomas, aaM phi occur in healing wounds and chronic inflammation. In contrast to caM phi-dominated lesions, aaM phi-rich lesions are highly vascularized. In order to determine their angiogenic potential in vitro, these M phi subsets as well as unstimulated control macrophages (coM phi) were analyzed by RT-PCR for mRNA expression of 10 angiogenic factors after 3 and 6 days of culture. Early during activation, caM phi and coM phi expressed equal levels of 8 of 10 angiogenic factors (PDGF-A, MK, TNF-alpha, TGF-beta 1, PDGF-B, HGF, TGF-alpha, IGF-1), while aaM phi showed expression of only 4 of these factors (TGF-beta 1, PDGF-B, HGF, GF-1). After maturation, TGF-alpha and IGF-1 showed a shift in mRNA expression from caM phi to aaM phi resulting in a considerably enhanced expression of these factors in day-6 aaM phi as compared to day-6 caM phi and coM phi while PDGF-A, MK, and TNF-alpha remained suppressed in day 6 aaM phi. In all M phi subsets including controls, mRNA expression of aFGF and bFGF was minimal or absent while TGFG-beta 1, HGF, and ODGF-B were constitutively expressed. In order to functionally integrate angiogenic factor mRNA expression profiles, mitogenic activity of M phi subsets towards microvascular endothelium was assessed by cocultivation. Coculture experiments revealed that endothelial proliferation induced by aaM phi was 3.0-3.5x higher than induced by caM phi. In conclusion, mature aaM phi are well equipped to play an important role in protracted M phi-associated angiogenic processes. Presumably due to expression of predominantly angio-inhibitory cytokines such as TNF-alpha by caM phi but much less by aaM phi, caM phi exhibit only a low angiogenic potential in vitro and in vivo despite considerable expression of angiogenic factor mRNA.
巨噬细胞（M phi）在炎症、伤口修复和肿瘤生长过程中的血管生成中起重要作用。然而，尚未对特征明确的M phi亚群，如干扰素-γ诱导的经典活化（ca）M phi或白细胞介素-4/糖皮质激素诱导的替代活化（aa）M phi与血管生成的正相关或负相关进行彻底研究。虽然caM phi在早期炎症反应和高周转率肉芽肿中占主导，但aaM phi出现在愈合伤口和慢性炎症中。与以caM phi为主的病变不同，富含aaM phi的病变血管高度丰富。为了确定它们在体外的血管生成潜力，在培养3天和6天后，通过逆转录聚合酶链反应（RT-PCR）分析这些M phi亚群以及未刺激的对照巨噬细胞（coM phi）中10种血管生成因子的mRNA表达。在活化早期，caM phi和coM phi表达10种血管生成因子中的8种（血小板衍生生长因子-A、巨噬细胞趋化因子、肿瘤坏死因子-α、转化生长因子-β1、血小板衍生生长因子-B、肝细胞生长因子、转化生长因子-α、胰岛素样生长因子-1）的水平相等，而aaM phi仅表达其中4种因子（转化生长因子-β1、血小板衍生生长因子-B、肝细胞生长因子、胰岛素样生长因子-1）。成熟后，转化生长因子-α和胰岛素样生长因子-1的mRNA表达从caM phi转移到aaM phi，导致与第6天的caM phi和coM phi相比，第6天的aaM phi中这些因子的表达显著增强，而血小板衍生生长因子-A、巨噬细胞趋化因子和肿瘤坏死因子-α在第6天的aaM phi中仍受抑制。在包括对照在内的所有M phi亚群中，酸性成纤维细胞生长因子（aFGF）和碱性成纤维细胞生长因子（bFGF）的mRNA表达极少或不存在，而转化生长因子-β1、肝细胞生长因子和血小板衍生生长因子-B则持续表达。为了在功能上整合血管生成因子mRNA表达谱，通过共培养评估M phi亚群对微血管内皮的促有丝分裂活性。共培养实验表明，aaM phi诱导的内皮细胞增殖比caM phi诱导的高3.0-3.5倍。总之，成熟的aaM phi具备在与M phi相关的长期血管生成过程中发挥重要作用的能力。可能由于caM phi主要表达血管抑制性细胞因子如肿瘤坏死因子-α，而aaM phi表达较少，尽管血管生成因子mRNA表达相当，但caM phi在体外和体内仅表现出较低的血管生成潜力。
