The natural sesquiterpene lactones arglabin, grosheimin, agracin, parthenolide, and estafiatin inhibit T cell receptor (TCR) activation

Abstract

Inhibition of the T cell receptor (TCR) pathway represents an effective strategy for the treatment of T cell-mediated inflammatory and autoimmune diseases. To identify natural compounds that could inhibit inflammatory T cell responses, we screened 13 sesquiterpene lactones, including achillin, arglabin, argolide, argracin, 3β-hydroxyarhalin, artesin, artemisinin, estafiatin, grosheimin, grossmisin, leucomisine, parthenolide, and taurine, for their ability to modulate activation-induced Ca mobilization in Jurkat T cells. Five of the compounds (arglabin, grosheimin, argracin, parthenolide, and estafiatin) inhibited anti-CD3-induced mobilization of intercellular Ca ([Ca⁺]) in Jurkat cells, with the most potent being parthenolide and argacin (IC = 5.6 and 6.1 μM, respectively). Likewise, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in activated Jurkat cells was inhibited by these five compounds, with the most potent being parthenolide and estafiatin (IC = 13.8 and 15.4 μM, respectively). These compounds also inhibited ERK1/2 phosphorylation in primary human T cells and depleted intracellular glutathione. In contrast, none of the sesquiterpene lactones inhibited ERK1/2 phosphorylation in HL60 cells transfected with N-formyl peptide receptor 2 (FPR2) and stimulated with the FPR2 peptide agonist WKYMVM, indicating specificity for T cell activation. Estafiatin, a representative sesquiterpene lactone, was also profiled in a cell-based phosphokinase array for 43 kinase phosphorylation sites, as well as in a cell-free competition binding assay for its ability to compete with an active-site directed ligand for 95 different protein kinases. Besides inhibition of ERK1/2 phosphorylation, estafiatin also inhibited phosphorylation of p53, AMPKα1, CREB, and p27 elicited by TCR activation in Jurkat cells, but it did not bind to any of 95 kinases evaluated. These results suggest that arglabin, grosheimin, agracin, parthenolide, and estafiatin can selectively inhibit initial phases of TCR activation and may be natural compounds with previously undescribed immunotherapeutic properties.

Parthenolide in Danish biodynamic and organic milk: A new source of exposure to an allergenic sesquiterpene lactone

“…Likewise, some SLs may cause livestock poisoning, and tansy is one of the plants that has been reported to be poisonous . PHL is an alkylating SL, owing to an α‐methylene‐γ‐butyrolactone moiety and an electrophilic epoxide group in its structure (Figure ); hence, PHL is reactive towards, for example, thiols in proteins, which may explain its anti‐inflammatory and cytotoxic properties in addition to its allergenic potential . Both PHL and its synthetic analogue dimethylaminoparthenolide are promising anticancer agents .…”

“…7 PHL is an alkylating SL, owing to an α-methylene-γ-butyrolactone moiety and an electrophilic epoxide group in its structure ( Figure 1); hence, PHL is reactive towards, for example, thiols in proteins, which may explain its anti-inflammatory and cytotoxic properties in addition to its allergenic potential. 19,20 Both PHL and its synthetic analogue dimethylaminoparthenolide are promising anticancer agents. 7,21,22 In a phase I dose escalation trial in patients with cancer, PHL at a daily dose of up to 4 mg orally was well tolerated.…”

Current status and prospects of plant biotechnology in Kazakhstan

“…Up to today, 72 new original herbal remedies have been developed and introduced into production. More than 2000 new derivatives have been synthesised, a number of which showed significant antimicrobial, antiviral, antifungal, antitumor, analgesic, phagocyte-stimulating, anthelmintic, neurotropic and other types of activities (Adekenov 2016(Adekenov , 2017Schepetkin et al 2018;Suleimenov et al 2010).…”

Detailed 1H and 13C NMR structural assignments of four sesquiterpene lactones isolated from Eremanthus elaeagnus (Asteraceae)

“…Sesquiterpene lactones (SLs) constitute an important class of natural products (NPs) that are abundant in plants of the Asteraceae family and possess a broad spectrum of biological activities, including anticancer, antibacterial, antifungal, anti-inflammatory, and immunomodulatory activities. [1][2][3][4][5][6] SLs include a variety of carbocyclic skeletons that display different biologically active chemical structures, as reported by papers published since the 1960s, when the first SLs were isolated. [7][8][9][10] Several SLs were isolated prior to the introduction of nuclear magnetic resonance (NMR) methodologies, which are related to the parallel development of new techniques and equipment evolution, such as highfield magnet, inverse detection, pulse field gradient, and new pulse sequences.…”