Coupling of boswellic acid-induced Ca~(2+) mobilisation and MAPK activation to lipid metabolism and peroxide formation in human leucocytes

摘要

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.