title: 3-O-acetyl-11-keto-boswellic acid decreases basal intracellular Ca2+ levels and inhibits agonist-induced Ca2+ mobilization and mitogen-activated protein kinase activation in human monocytic cells.
abstract: 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 microM) 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)-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+)](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 proinflammatory stimuli. Interruption of these events may represent a possible mechanism underlying the reported anti-inflammatory properties of AKBA.
authors.affiliation: Department of Pharmaceutical Analysis, Institute of Pharmacy, Eberhard-Karls-University Tubingen, Auf der Morgenstelle 8, 72076 Tubingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Poeckel
authors.forename: Lars
authors.initials: L
authors.lastname: Tausch
authors.forename: Sven
authors.initials: S
authors.lastname: George
authors.forename: Johann
authors.initials: J
authors.lastname: Jauch
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D000893:Anti-Inflammatory Agents; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007293:Inosine Triphosphate / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D002120:Calcium Channel Agonists; D010972:Platelet Activating Factor; D014315:Triterpenes; C094432:acetyl-11-ketoboswellic acid; D007293:Inosine Triphosphate; D009240:N-Formylmethionine Leucyl-Phenylalanine; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium