Triterpenoids as Anti-inflammatory Compounds of Natural Origin

Despite the progress in understanding the molecular mechanisms underlying chronic inflammation, the current treatment options are not satisfactory. The transcription factor NF-κB, a key player in the development and progression of chronic inflammation, is considered a promising target for therapeutic intervention. In Ayurvedic medicine, extracts from the oleogum resin from Boswellia serrata are being used as anti-inflammatory remedies. After purification to chemical homogeneity, we have identified a number of pentacyclic triterpenoids including acetyl-boswellic acids (ABAs). Using LPS as an activator of human monocytes, we found that ABAs inhibit NF-κB signaling. We identified specific inhibitory effects on IκB kinase (IKK), which is pivotal for the degradation of the NF-κB inhibitor IκB, as well as the phosphorylation of p65, two steps essential for NF-κB activation and the subsequent cytokine expression. Using active human recombinant IKKα and IKKβ, we positively confirmed the direct effect of the ABAs on the IKK complex. We further studied the effects of systemically applied AKβBA on the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE^−/−) mice. Atherosclerotic lesion formation was accelerated in those animals by weekly intraperitoneal lipopolysaccharide (LPS) injections. LPS alone increased the atherosclerotic lesion size by two-fold and treatment with AKβBA significantly reduced it by about 50%. Daily treatment of the mice with AKβBA potently inhibited the NF-κB activation in atherosclerotic plaques and led to significant down-regulation of several NF-κB-dependent genes such as MCP-1, MCP-3, IL-1α, MIP-2, VEGF and TF. By contrast, AKβBA did not affect the plasma concentrations of triglycerides, total cholesterol, and various subsets of lymphocyte-derived cytokines. Thus, the inhibition of NF-κB signalling by constituents of the oleogum resins from Boswellia species might represent an alternative for conventional treatments of chronic inflammatory diseases such as atherosclerosis. Acknowledgements: This work was supported by the Deutsche Krebshilfe.