3-O-Acetyl-11-keto-boswellic Acid Decreases Basal Intracellular Ca~(2+)Levels and Inhibits Agonist-Induced Ca~(2+)Mobilization and Mitogen-Activated Protein Kinase Activation in Human Monocytic Cells

摘要

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+)]_i)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 muM)decreased the basal [Ca~(2+)]_i,in resting MM6 cells but also in cells where [Ca~(2+)]_i had been elevated by stimulation with platelet-activating factor(PAF).AKBA also strongly suppressed the subsequent elevation of [Ca~(2+)]_i,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)-benzenesulfon-amide,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 jn fMLP-stimulated MM6 cells.Although the effects of AKBA could be mimicked by the putative phospholipase C(PLC)inhibitor U-73122(1-[6-[[17 beta-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)-benzenesul-fonamide was hardly diminished by AKBA.Inhibitor studies indicate that AKBA may decrease [Ca~(2+)]_i 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 proinflam-matory stimuli.Interruption of these events may represent a possible mechanism underlying the reported anti-inflammatory properties of AKBA.