Poeckel Daniel, Tausch Lars, George Sven, Jauch Johann, Werz Oliver
Department of Pharmaceutical Analysis, Institute of Pharmacy, Eberhard-Karls-University Tubingen, Auf der Morgenstelle 8, 72076 Tubingen, Germany.
J Pharmacol Exp Ther. 2006 Jan;316(1):224-32. doi: 10.1124/jpet.105.089466. Epub 2005 Sep 20.
Previously, we showed that 11-keto-boswellic acid and 3-O-acetyl-11-keto-BA (AKBA) stimulate Ca(2+) mobilization and activate mitogen-activated protein kinases (MAPKs) in human polymorphonuclear leukocytes (PMNLs). Here, we addressed the effects of boswellic acids on the intracellular Ca(2+) concentration (Ca(2+)) and on the activation of p38(MAPK) and extracellular signal-regulated kinase (ERK) in the human monocytic cell line Mono Mac (MM) 6. In contrast to PMNLs, AKBA concentration dependently (1-30 microM) decreased the basal Ca(2+) in resting MM6 cells but also in cells where Ca(2+) had been elevated by stimulation with platelet-activating factor (PAF). AKBA also strongly suppressed the subsequent elevation of Ca(2+) induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP), PAF, or by the direct phospholipase C activator 2,4, 6-trimethyl-N-(meta-3-trifluoromethyl-phenyl)-benzenesulfonamide, but AKBA failed to prevent Ca(2+) signals induced by thapsigargin or ionomycin. Suppression of Ca(2+) homeostasis by AKBA was also observed in primary monocytes, isolated from human blood. Moreover, AKBA inhibited the activation of p38(MAPK) and ERKs in fMLP-stimulated MM6 cells. Although the effects of AKBA could be mimicked by the putative phospholipase C (PLC) inhibitor U-73122 (1-[6-[[17beta-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), AKBA appears to operate independent of PLC activity since the release of intracellular inositol-1,4,5-trisphosphate evoked by 2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl)-benzenesulfonamide was hardly diminished by AKBA. Inhibitor studies indicate that AKBA may decrease Ca(2+) by blocking store-operated Ca(2+) and/or nonselective cation channels. Together, AKBA interferes with pivotal signaling events in monocytic cells that are usually required for monocyte activation by proinflammatory stimuli. Interruption of these events may represent a possible mechanism underlying the reported anti-inflammatory properties of AKBA.
此前，我们发现11-酮基乳香酸和3-O-乙酰基-11-酮基乳香酸（AKBA）可刺激人多形核白细胞（PMNLs）中的Ca(2+)动员并激活丝裂原活化蛋白激酶（MAPKs）。在此，我们研究了乳香酸对人单核细胞系Mono Mac（MM）6细胞内Ca(2+)浓度（Ca(2+)）以及p38(MAPK)和细胞外信号调节激酶（ERK）激活的影响。与PMNLs不同，AKBA浓度依赖性地（1 - 30 microM）降低了静息MM6细胞中的基础Ca(2+)，在通过血小板活化因子（PAF）刺激使Ca(2+)升高的细胞中也是如此。AKBA还强烈抑制了由N-甲酰甲硫氨酰亮氨酰苯丙氨酸（fMLP）、PAF或直接磷脂酶C激活剂2,4,6-三甲基-N-（间-3-三氟甲基苯基）苯磺酰胺诱导的随后的Ca(2+)升高，但AKBA未能阻止由毒胡萝卜素或离子霉素诱导的Ca(2+)信号。在从人血液中分离的原代单核细胞中也观察到AKBA对Ca(2+)稳态的抑制作用。此外，AKBA抑制了fMLP刺激的MM6细胞中p38(MAPK)和ERK的激活。尽管AKBA的作用可被假定的磷脂酶C（PLC）抑制剂U-73122（1-[6-[[17β-甲氧基雌甾-1,3,5(10)-三烯-17-基]氨基]己基]-1H-吡咯-2,5-二酮）模拟，但AKBA似乎独立于PLC活性起作用，因为2,4,6-三甲基-N-（间-3-三氟甲基苯基）苯磺酰胺诱发的细胞内肌醇-1,4,5-三磷酸释放几乎未被AKBA减弱。抑制剂研究表明，AKBA可能通过阻断储存操纵性Ca(2+)通道和/或非选择性阳离子通道来降低Ca(2+)。总之，AKBA干扰了单核细胞中通常由促炎刺激激活单核细胞所需的关键信号事件。这些事件的中断可能是AKBA所报道的抗炎特性的潜在机制。
