Helenalin, an Anti-Inflammatory Sesquiterpene Lactone from Arnica, Selectively Inhibits Transcription Factor NF-κB

Abstract

Alcoholic extracts prepared form Arnicae flos, the collective name for flowerheads from Arnica montana and A. chamissonis ssp. foliosa, are used therapeutically as anti-inflammatory remedies. The active ingredients mediating the pharmacological effect are mainly sesquiterpene lactones, such as helenalin, 11alpha,13-dihydrohelenalin, chamissonolid and their ester derivatives. While these compounds affect various cellular processes, current data do not fully explain how sesquiterpene lactones exert their anti-inflammatory effect. We show here that helenalin, and, to a much lesser degree, 11alpha,13-dihydrohelenalin and chamissonolid, inhibit activation of transcription factor NF-kappaB. This difference in efficacy, which correlates with the compounds' anti-inflammatory potency in vivo, may be explained by differences in structure and conformation. NF-kappaB, which resides in an inactive, cytoplasmic complex in unstimulated cells, is activated by phosphorylation and degradation of its inhibitory subunit, IkappaB. Helenalin inhibits NF-kappaB activation in response to four different stimuli in T-cells, B-cells and epithelial cells and abrogates kappaB-driven gene expression. This inhibition is selective, as the activity of four other transcription factors, Oct-1, TBP, Sp1 and STAT 5 was not affected. We show that inhibition is not due to a direct modification of the active NF-kappaB heterodimer. Rather, helenalin modifies the NF-kappaB/IkappaB complex, preventing the release of IkappaB. These data suggest a molecular mechanism for the anti-inflammatory effect of sesquiterpene lactones, which differs from that of other nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin and acetyl salicylic acid.

Melanoma cell migration to type IV collagen requires activation of NF-κB

“…Furthermore, the complex was supershifted by polyclonal sera against p50 and p65 ( Figure 4b; lanes 1-4) but not control serum, which recognized C/EBPb (Figure 4b; lanes 5 and 6). Treating cells with NF-kB inhibitor Helenalin (10 mm), which specifically and irreversibly alkylates the p65 subunit of NF-kB thus disrupting its binding activity (Lyss et al, 1997(Lyss et al, , 1998, attenuated NF-kB induction following CIV treatment ( Figure 4a; lanes 3, 7, and 11). Decreased binding was also observed with a second inhibitor of NF-kB activation, SN-50 (50 mg/ml; Figure 4a; lanes 4, 8, and 12).…”

“…In order to determine whether the activation of NF-kB was critical to cell migration in response to CIV, A2058 cells were treated with NF-kB inhibitors Helenalin and SN-50 and assessed for migration. Helenalin, a plant-derived sesquiterpene lactone, specifically and irreversibly alkylates p65 subunit of NF-kB to block DNA binding (Lyss et al, 1997(Lyss et al, , 1998. SN-50 is a synthetic peptide that prevents the translocation of activated NF-kB complex to the nucleus .…”

A Preferential Role for STAT5, not Constitutively Active STAT3, in Promoting Survival of a Human Lymphoid Tumor

“…Because Bcl10, Traf2, and Traf5 act as upstream activators of NF-B and regulate the activity of the I B kinase complex (61,65), one possible model to explain these findings is that STAT5 depletion reduces the expression of these effectors and consequent NF-B activation that is important for cell survival. Indeed, treatment of YT cells with Helenalin that selectively alkylates the p65 subunit of NF-B and interferes with its DNA-binding activity, but not STAT5 activity (67), greatly reduced YT cell viability in a dose-dependent fashion. These data suggest that STAT5 and NF-B may act in concert to maintain YT cell survival.…”

Endophytic Streptomyces in the traditional medicinal plant Arnica montana L.: secondary metabolites and biological activity

“…Sesquiterpene lactones such as helenalin, 11α,13-dihydrohelenalin and their esters are the most effective compounds responsible for the utilised anti-inflammatory activity (Teuscher et al 2009;Merfort 2010). These compounds were proven to inhibit the transcription factor NF-κB thus targeting the inflammatory processes at a central point (Lyss et al 1997;García-Piñeres et al 2001). Additionally, those molecules exert an antibacterial activity against gram-positive bacteria (Lee et al 1977).…”