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

• Published in: Phytochemistry (Oxford) Vol. 146; pp. 36 - 46
• Main Authors: Schepetkin, Igor A., Kirpotina, Liliya N., Mitchell, Pete T., Kishkentaeva, Аnarkul S., Shaimerdenova, Zhanar R., Atazhanova, Gayane A., Adekenov, Sergazy M., Quinn, Mark T.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2018
• Subjects: Biological Products - chemistry; Biological Products - isolation & purification; Biological Products - pharmacology; Calcium flux; Cell Survival - drug effects; Dose-Response Relationship, Drug; Glutathione; Humans; Jurkat T cells; Kinase; Neutrophils - drug effects; Phosphorylation; Receptors, Antigen, T-Cell - antagonists & inhibitors; Sesquiterpene lactones; Sesquiterpenes - chemistry; Sesquiterpenes - isolation & purification; Sesquiterpenes - pharmacology; Sesquiterpenes, Guaiane - chemistry; Sesquiterpenes, Guaiane - isolation & purification; Sesquiterpenes, Guaiane - pharmacology; Structure-Activity Relationship; T cell receptor; T-Lymphocytes - drug effects; Tumor Cells, Cultured; Phosphorylation; TCR; T cell receptor; DMSO; GEE; PLC; Jurkat T cells; FPR; MAPK; SERCA; IP3; Sesquiterpene lactones; Kinase; ITAM; FBS; HBSS; Calcium flux; GSH; Glutathione; ERK; ELISA
• ISSN: 0031-9422; 1873-3700
• DOI: 10.1016/j.phytochem.2017.11.010

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 Ca2+ mobilization in Jurkat T cells. Five of the compounds (arglabin, grosheimin, argracin, parthenolide, and estafiatin) inhibited anti-CD3-induced mobilization of intercellular Ca2+ ([Ca2⁺]i) in Jurkat cells, with the most potent being parthenolide and argacin (IC50 = 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 (IC50 = 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. [Display omitted] •Thirteen natural sesquiterpene lactones were evaluated for their ability to inhibit inflammatory T cell responses.•Five natural sesquiterpene lactones inhibited early steps in T cell activation, including several kinases.•The active natural sesquiterpene lactones also depleted T cell intracellular glutathione levels.•The ability to inhibit TCR activation suggests these natural compounds may have novel immunotherapeutic properties.