Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada.
Am J Physiol Gastrointest Liver Physiol. 2011 Sep;301(3):G487-97. doi: 10.1152/ajpgi.00042.2011. Epub 2011 Jun 9.
The macrophage plays a major role in the induction and resolution phases of inflammation; however, how lipid mediator-derived signals may modulate macrophage function in the resolution of inflammation driven by microbes (e.g., in inflammatory bowel disease) is not well understood. We examined the effects of aspirin-triggered lipoxin (ATL), a stable analog of lipoxin A(4), on the antimicrobial responses of human peripheral blood mononuclear cell-derived macrophages and the monocytic THP-1 cell line. Additionally, we assessed the expression and localization of the lipoxin receptor, formyl peptide receptor 2 (FPR2), in colonic mucosal biopsies from patients with Crohn's disease to determine whether the capacity for lipoxin signaling is altered in inflammatory bowel disease. We found that THP-1 cells treated with ATL (100 nM) displayed increased phagocytosis of inert fluorescent beads and Escherichia coli in a scavenger receptor- and PI3K-dependent, opsonization-independent manner. This ATL-induced increase in phagocytosis was also observed in primary human macrophages, where it was associated with an inhibition of E. coli-induced IL-1β and IL-8 production. Finally, we found that FPR2 gene expression was increased approximately sixfold in the colon of patients with Crohn's disease, a finding reproduced in vitro by the treatment of THP-1 cells with interferon-γ or lipopolysaccharide. These results suggest that lipoxin signaling is upregulated in inflammatory environments, and, in addition to their known role in tissue resolution following injury, lipoxins can enhance macrophage clearance of invading microbes.
巨噬细胞在炎症的诱导和消退阶段发挥主要作用；然而，脂质介质衍生的信号如何调节巨噬细胞在由微生物驱动的炎症消退中的功能（例如，在炎症性肠病中）还不太清楚。我们研究了阿司匹林触发的脂氧素（ATL），即脂氧素 A（4）的稳定类似物，对人外周血单核细胞衍生的巨噬细胞和单核细胞 THP-1 细胞系的抗菌反应的影响。此外，我们评估了脂氧素受体，甲酰肽受体 2（FPR2）在克罗恩病患者结肠黏膜活检中的表达和定位，以确定脂氧素信号转导的能力是否在炎症性肠病中发生改变。我们发现，用 ATL（100 nM）处理的 THP-1 细胞以依赖于清道夫受体和 PI3K、不依赖于调理作用的方式显示出对惰性荧光珠和大肠杆菌的吞噬作用增加。这种 ATL 诱导的吞噬作用增加也在原代人巨噬细胞中观察到，其中与大肠杆菌诱导的 IL-1β和 IL-8 产生的抑制有关。最后，我们发现 FPR2 基因表达在克罗恩病患者的结肠中增加了约六倍，这一发现可以通过用干扰素-γ或脂多糖处理 THP-1 细胞在体外重现。这些结果表明，脂氧素信号在炎症环境中上调，除了它们在受伤后组织消退中的已知作用外，脂氧素还可以增强巨噬细胞清除入侵的微生物。
