Acetyl-Boswellic Acids Inhibit Lipopolysaccharide-Mediated TNF-α Induction in Monocytes by Direct Interaction with IκB Kinases

Abstract

Expression of proinflammatory cytokines by monocytes is tightly regulated by transcription factors such as NF-κB. In this study, we show that, in LPS-stimulated human peripheral monocytes, the pentacyclic triterpenes acetyl-α-boswellic acid (AαBA) and acetyl-11-keto-β-boswellic acid (AKβBA) down-regulate the TNF-α expression. AαBA and AKβBA inhibited NF-κB signaling both in LPS-stimulated monocytes as detected by EMSA, as well as in a NF-κB-dependent luciferase gene reporter assay. By contrast, the luciferase expression driven by the IFN-stimulated response element was unaffected, implying specificity of the inhibitory effect observed. Both AαBA and AKβBA did not affect binding of recombinant p50/p65 and p50/c-Rel dimers to DNA binding sites as analyzed by surface plasmon resonance. Instead, both pentacyclic triterpenes inhibited the LPS-induced degradation of IκBα, as well as phosphorylation of p65 at Ser536 and its nuclear translocation. AαBA and AKβBA inhibited specifically the phosphorylation of recombinant IκBα and p65 by IκBα kinases (IKKs) immunoprecipitated from LPS-stimulated monocytes. In line with this, AαBA and AKβBA also bound to and inhibited the activities of active human recombinant GST-IKKα and His-IKKβ. The LPS-triggered induction of TNF-α in monocytes is dependent on IKK activity, as confirmed by IKK-specific antisense oligodeoxynucleotides. Thus, via their direct inhibitory effects on IKK, AαBA and AKβBA convey inhibition of NF-κB and subsequent down-regulation of TNF-α expression in activated human monocytes. These findings provide a molecular basis for the anti-inflammatory properties ascribed to AαBA- and AKβBA-containing drugs and suggest acetyl-boswellic acids as tools for the development of novel therapeutic interventions.

Evaluation of the Efficacy of Ginger, Arabic Gum, andBoswelliain Acute and Chronic Renal Failure

“…55 Accordingly, it is speculated that BAs may exert their anti-inflammatory effect mainly by inhibiting the release of proinflammatory LT products from leukocytes and platelets 55 and by the inhibition of NF-κβ and subsequent downregulation of TNF-α expression in activated monocytes. 56 The protective effect of Boswellia against RIR is not attributed to the modulation of oxidative stress as it does not affect serum MDA or renal SOD levels. But it may block its subsequent inflammatory effect.…”

Inhibition of microsomal prostaglandin E2 synthase‐1 as a molecular basis for the anti‐inflammatory actions of boswellic acids from frankincense

“…The inhibition of cathepsin G may also explain the slight but still significant reduction of oedema formation and cell infiltration upon pretreatment with Ab-BA, which was the least potent inhibitor of mPGES1 and failed to suppress PGE2 formation in whole blood. Similarly, interference with other pro-inflammatory components, such as cytokines and transcription factors (Syrovets et al, 2005;Kunnumakkara et al, 2009), may suppress COX-2 induction, explaining the reduced 6-keto PGF 1a levels in the exudates of KBA-and Ab-BA-treated rats.…”

“…Pilot clinical studies have suggested some efficacy of frankincense preparations in the treatment of osteoarthritis (OA), rheumatoid arthritis (RA), inflammatory bowel diseases, asthma and cancer (see Ammon, 2006;Poeckel and Werz, 2006). Molecular mechanisms responsible for these therapeutics effects have been mainly attributed to the interference of 3-O-acetyl-11-keto-b-BA (AKBA) with signalling pathways including the nuclear factor-kB route (Syrovets et al, 2005), mitogen-activated protein kinase pathway and Ca 2+ signalling (Poeckel et al, 2006a) as well as targeting human leukocyte elastase (HLE) (Safayhi et al, 1997), 5-lipoxygenase (5-LOX) (Safayhi et al, 1992), platelet-type 12-lipoxygenase (12S-LOX) (Poeckel et al, 2006b) and COX-1 . However, in vivo studies confirming the pharmacological relevance of these proposed target interactions are still missing, and the efficacy of defined BAs in in vivo models of inflammation remains to be assessed.…”

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

“…The results showed that AKBA potentiated apoptosis induced by TNF-a and chemotherapeutic agents, inhibited TNF-a-induced cell invasion, and abrogated RANKL-induced osteoclastogenesis through inhibition of NF-jB activation. AKBA inhibited lipopolysaccharide induced production of TNF-a in monocytes was mediated by suppression of IjBa kinases [72]. In vivo treatment with AKBA inhibited the growth and metastasis of colorectal cancer in orthotopically implanted tumors in nude mice.…”