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 þ mobilisation in human polymorphonuclear leucocytes (PMNL). 2 In this study, we attempted to connect the activation of MAPK and mobilisation of Ca 2 þ 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 þ -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 þ 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 þ 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 þ 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-formylmethionyl-leucyl-phenylalanine or platelet-activating factor.

We have recently shown that in polymorphonuclear leukocytes, 11‐keto boswellic acids (KBAs) induce Ca2+ mobilisation and activation of mitogen‐activated protein kinases (MAPK). Here we addressed the effects of BAs on central signalling pathways in human platelets and on various platelet functions. We found that β‐BA (10 μM), the 11‐methylene analogue of KBA, caused a pronounced mobilisation of Ca2+ from internal stores and induced the phosphorylation of p38 MAPK, extracellular signal‐regulated kinase (ERK)2, and Akt. These effects of β‐BA were concentration dependent, and the magnitude of the responses was comparable to those obtained after platelet stimulation with thrombin or collagen. Based on inhibitor studies, β‐BA triggers Ca2+ mobilisation via the phospholipase (PL)C/inositol‐1,4,5‐trisphosphate pathway, and involves Src family kinase signalling. Investigation of platelet functions revealed that β‐BA (10 μM) strongly stimulates the platelet‐induced generation of thrombin in an ex‐vivo in‐vitro model, the liberation of arachidonic acid (AA), and induces platelet aggregation in a Ca2+‐dependent manner. In contrast to β‐BA, the 11‐keto‐BAs (KBA or AKBA) evoke only moderate Ca2+ mobilisation and activate p38 MAPK, but fail to induce phosphorylation of ERK2 or Akt, and do not cause aggregation or significant generation of thrombin. In summary, β‐BA potently induces Ca2+ mobilisation as well as the activation of pivotal protein kinases, and elicits functional platelet responses such as thrombin generation, liberation of AA, and aggregation. British Journal of Pharmacology (2005) 146, 514–524. doi:

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