Riemann Anne, Wußling Hanna, Loppnow Harald, Fu Hang, Reime Sarah, Thews Oliver
Julius-Bernstein-Institute of Physiology, University Halle-Wittenberg, Germany.
Julius-Bernstein-Institute of Physiology, University Halle-Wittenberg, Germany.
Biochim Biophys Acta. 2016 Jan;1862(1):72-81. doi: 10.1016/j.bbadis.2015.10.017. Epub 2015 Oct 22.
Inflammation, ischemia or the microenvironment of solid tumors is often accompanied by a reduction of extracellular pH (acidosis) that stresses the cells and acts on cellular signaling and transcription. The effect of acidosis on the expression of various inflammatory markers, on functional parameters (migration, phagocytic activity) and on signaling pathways involved was studied in monocytic cells and macrophages. In monocytic cell lines acidosis led to a reduction in expression of most of the inflammatory mediators, namely IL-1ß, IL-6, TNF-α, MCP-1, COX-2 and osteopontin. In primary human monocytes MCP-1 and TNF-α were reduced but COX-2 and IL-6 were increased. In RAW264.7 macrophage cell line IL-1ß, COX-2 and iNOS expression was increased, whereas MCP-1 was reduced similar to the effect in monocytic cells. For primary human monocyte-derived macrophages the regulation of inflammatory markers by acidosis depended on activation state, except for the acidosis-induced downregulation of MCP-1 and TNF-α. Acidosis affected functional immune cell behavior when looking at phagocytic activity which was increased in a time-dependent manner, but cellular motility was not changed. Neither ERK1/2 nor CREB signaling was stimulated by the reduction of extracellular pH. However, p38 was activated by acidosis in RAW264.7 cells and this activation was critical for the induction of IL-1ß, COX-2 and iNOS expression. In conclusion, acidosis may impede the recruitment of immune cells, but fosters inflammation when macrophages are present by increasing the level of COX-2 and iNOS and by functionally forcing up the phagocytic activity.
炎症、缺血或实体瘤的微环境常伴有细胞外pH值降低（酸中毒），这会给细胞带来压力，并作用于细胞信号传导和转录过程。研究了酸中毒对单核细胞和巨噬细胞中各种炎症标志物表达、功能参数（迁移、吞噬活性）以及相关信号通路的影响。在单核细胞系中，酸中毒导致大多数炎症介质的表达减少，即白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、单核细胞趋化蛋白-1（MCP-1）、环氧化酶-2（COX-2）和骨桥蛋白。在原代人单核细胞中，MCP-1和TNF-α减少，但COX-2和IL-6增加。在RAW264.7巨噬细胞系中，IL-1β、COX-2和诱导型一氧化氮合酶（iNOS）的表达增加，而MCP-1减少，这与在单核细胞中的作用类似。对于原代人单核细胞衍生的巨噬细胞，除了酸中毒诱导的MCP-1和TNF-α下调外，酸中毒对炎症标志物的调节取决于激活状态。从吞噬活性来看，酸中毒影响功能性免疫细胞行为，吞噬活性呈时间依赖性增加，但细胞运动性未改变。细胞外pH值降低既未刺激细胞外信号调节激酶1/2（ERK1/2）信号通路，也未刺激cAMP反应元件结合蛋白（CREB）信号通路。然而，在RAW264.7细胞中，酸中毒激活了p38，这种激活对于诱导IL-1β、COX-2和iNOS的表达至关重要。总之，酸中毒可能会阻碍免疫细胞的募集，但当巨噬细胞存在时，通过增加COX-2和iNOS的水平以及功能性地增强吞噬活性来促进炎症。
