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

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+)](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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents
  • Blotting, Western
  • Calcium / metabolism*
  • Calcium Channel Agonists / pharmacology*
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Humans
  • In Vitro Techniques
  • Inosine Triphosphate / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Monocytes / drug effects
  • Monocytes / enzymology
  • Monocytes / metabolism*
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Platelet Activating Factor / pharmacology
  • Triterpenes / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors


  • Anti-Inflammatory Agents
  • Calcium Channel Agonists
  • Platelet Activating Factor
  • Triterpenes
  • acetyl-11-ketoboswellic acid
  • Inosine Triphosphate
  • N-Formylmethionine Leucyl-Phenylalanine
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Calcium