Coupling of boswellic acid-induced Ca2+ mobilisation and MAPK activation to lipid metabolism and peroxide formation in human leucocytes.
1. We have previously shown that 11-keto boswellic acids (11-keto-BAs), the active principles of Boswellia serrata gum resins, activate p38 MAPK and p42/44(MAPK) and stimulate Ca(2+) mobilisation in human polymorphonuclear leucocytes (PMNL). 2. In this study, we attempted to connect the activation of MAPK and mobilisation of Ca(2+) to functional responses of PMNL, including the formation of reactive oxygen species (ROS), release of arachidonic acid (AA), and leukotriene (LT) biosynthesis. 3. We found that, in PMNL, 11-keto-BAs stimulate the formation of ROS and cause release of AA as well as its transformation to LTs via 5-lipoxygenase. 4. Based on inhibitor studies, 11-keto-BA-induced ROS formation is Ca(2+)-dependent and is mediated by NADPH oxidase involving PI 3-K and p42/44(MAPK) signalling pathways. Also, the release of AA depends on Ca(2+) and p42/44(MAPK), whereas the pathways stimulating 5-LO are not readily apparent. 5. Pertussis toxin, which inactivates G(i/0) protein subunits, prevents MAPK activation and Ca(2+) mobilisation induced by 11-keto-BAs, implying the involvement of a G(i/0) protein in BA signalling. 6. Expanding studies on differentiated haematopoietic cell lines (HL60, Mono Mac 6, BL41-E-95-A) demonstrate that the ability of BAs to activate MAPK and to mobilise Ca(2+) may depend on the cell type or the differentiation status. 7. In summary, we conclude that BAs act via G(i/0) protein(s) stimulating signalling pathways that control functional leucocyte responses, in a similar way as chemoattractants, that is, N-formyl-methionyl-leucyl-phenylalanine or platelet-activating factor.
Altmann
Anja
A
Institute of Pharmaceutical Chemistry, University of Frankfurt, Marie-Curie Strasse 9, Frankfurt D-60439, Germany.
Poeckel
Daniel
D
Fischer
Lutz
L
Schubert-Zsilavecz
Manfred
M
Steinhilber
Dieter
D
Werz
Oliver
O
D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D008054:Lipid Peroxides; D017382:Reactive Oxygen Species; D014315:Triterpenes; C054625:boswellic acid; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases