Deoxyelephantopin, a natural sesquiterpene lactone, suppresses IL-2 production of ConA-activated T lymphocytes through inhibiting NF-κB and calcineurin/NFAT signaling

DET decreases the transcription and translation of IL-2 in ConA-activated T cells. • DET inhibits ConA-activated NF-κB pathway, but fails to suppress MAPK signaling. • DET dampens ConA-induced nuclear translocation of NFAT. • DET directly suppresses calcineurin (CaN) activity not by reducing cytoplasmic Ca 2+ . • DET lowers serum IL-2 level of anti-CD3 antibody-treated mice. Deoxyelephantopin (DET) is a sesquiterpene lactone isolated from Elephantopus scaber , a traditional medicinal plant valued for its heat-clearing and detoxifying properties. As one of the major bioactive components, DET exhibits a variety of pharmacological activities, such as antitumor, antimicrobial, and anti-inflammatory effects. Nevertheless, its effect on T cell activation remains underexplored. Our study indicated that DET suppressed the proliferation and interleukin-2 (IL-2) production in T cells activated by various stimuli for T cell receptor (TCR)/CD3 signaling (i.e., concanavalin A (ConA), anti-CD3 antibody, and allogeneic major histocompatibility complex (MHC)). Mechanistically, DET lowered IL-2 mRNA level without affecting its stability in ConA-activated Jurkat T cells. Among three nuclear transcriptional pathways (mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), nuclear factor of activated T cells (NFAT)) triggered by ConA, DET did not suppress MAPK signaling, but significantly inhibited NF-κB activation by hindering inhibitor of kappa-B alpha (IκBα) phosphorylation and degradation, thereby preventing p65 nuclear translocation. Concurrently, DET could dampen the activation of NFAT signaling through inhibiting the activity of calcineurin (CaN) to impede NFAT nuclear translocation independent of decreasing cytoplasmic Ca 2+ (Ca 2+ [c] ). Unlike classical CaN inhibitors (CNIs), DET inhibits CaN activity without involving immunophilins. In vivo , DET could also reduce serum IL-2 level in acute T-cell activation mouse model induced by intravenous injection of anti-CD3 antibody. In conclusion, our findings reveal DET's dual mechanisms (NF-κB and NFAT inhibition) responsible for repressing IL-2 expression in the activated T cells, which may provide a promising candidate for the development of a novel IL-2 suppressive agent. Download: Download high-res image (270KB) Download: Download full-size image