Shimizu Toshiaki, Tomioka Haruaki
Department of Microbiology and Immunology, Shimane University School of Medicine, Izumo, Shimane, Japan.
Nihon Hansenbyo Gakkai Zasshi. 2009 Sep;78(3):283-91. doi: 10.5025/hansen.78.283.
Macrophages (M(phi)s) play a central role as anti-microbial effector cells in the expression of host resistance to mycobacterial infections. With respect to antimicrobial effector molecules of host M(phi) against mycobacterial pathogens, recent studies suggest the possibility that the reactive nitrogen intermediates (RNI)--and reactive oxygen intermediates-independent antimycobacterial mechanism(s) may be crucial for the antimycobacterial function of host M(phi). In this context, we previously found that free fatty acids (FFAs) such as arachidonic acid (AA) and linolenic acid exhibited potent antimicrobial activity against mycobacterial organisms, including Mycobacterium tuberculosis (MTB) and Mycobacterium avium complex (MAC). In addition, FFAs in combination with RNI played critical roles in manifestation of the activity of M(phi) against mycobacterial organisms. Moreover, our recent studies have shown the following findings. First, anti-MTB activity of IFN-gamma-activated M(phi)s was specifically blocked by arachidonyl trifluoromethylketone (aTFMK), an inhibitor of cytosolic phospholipase A2 (cPLA2). Second, ATP potentiated the anti-MAC bactericidal activity of M(phi)s cultivated in the presence of clarithromycin and rifamycin. This effect of ATP was closely related to intracellular Ca2+ mobilization and was specifically blocked by aTFMK. Third, intramacrophage translocation of membranous AA molecules to MAC-containing phagosomes was also specifically blocked by aTFMK. In the confocal microscopic observation of MAC-infected M(phi)s, ATP enhanced the intracellular translocation of cPLA2 into MAC-containing phagosomes. These findings suggest that FFAs (especially AA) produced by the enzymatic action of cPLA2 play important roles as antimycobacterial effectors in the expression of M(phi) antimicrobial activity against mycobacterial pathogens.
巨噬细胞（M(phi)s）作为抗微生物效应细胞，在宿主对分枝杆菌感染的抗性表达中发挥核心作用。关于宿主M(phi)针对分枝杆菌病原体的抗微生物效应分子，最近的研究表明，活性氮中间体（RNI）以及与活性氧中间体无关的抗分枝杆菌机制可能对宿主M(phi)的抗分枝杆菌功能至关重要。在此背景下，我们之前发现，诸如花生四烯酸（AA）和亚麻酸之类的游离脂肪酸（FFAs）对包括结核分枝杆菌（MTB）和鸟分枝杆菌复合体（MAC）在内的分枝杆菌生物体表现出强大的抗菌活性。此外，FFAs与RNI联合在M(phi)对分枝杆菌生物体的活性表现中发挥关键作用。而且，我们最近的研究有以下发现。首先，IFN-γ激活的M(phi)s的抗MTB活性被胞质磷脂酶A2（cPLA2）的抑制剂花生四烯酰三氟甲基酮（aTFMK）特异性阻断。其次，ATP增强了在克拉霉素和利福霉素存在下培养的M(phi)s对MAC的杀菌活性。ATP的这种作用与细胞内Ca2+动员密切相关，并被aTFMK特异性阻断。第三，膜性AA分子向含MAC吞噬体的巨噬细胞内转运也被aTFMK特异性阻断。在共聚焦显微镜观察MAC感染的M(phi)s时，ATP增强了cPLA2向含MAC吞噬体的细胞内转运。这些发现表明，由cPLA2的酶促作用产生的FFAs（尤其是AA）作为抗分枝杆菌效应分子，在M(phi)对分枝杆菌病原体的抗菌活性表达中发挥重要作用。
