Abstract
Loureirin B (LrB) is a constituent extracted from traditional Chinese medicine Resina Draconis. It has broad biological functions and an impressive immunosuppressive effect that has been supported by numerous studies. However, the molecular mechanisms underlying Loureirin B-induced immune suppression are not fully understood. We previously reported that Loureirin B inhibited KV1.3 channel, calcium ion (Ca2+) influx, and interleukin-2 (IL-2) secretion in Jurkat T cells. In this study, we applied CRISPR/Cas9 to edit KV1.3 coding gene KCNA3 and successfully generated a KV1.3 knockout (KO) cell model to determine whether KV1.3 KO was sufficient to block the Loureirin B-induced immunosuppressive effect. Surprisingly, we showed that Loureirin B could still inhibit Ca2+ influx and IL-2 secretion in the Jurkat T cells in the absence of KV1.3 although KO KV1.3 reduced about 50% of Ca2+ influx and 90% IL-2 secretion compared with that in the wild type cells. Further experiments showed that Loureirin B directly inhibited STIM1/Orai1 channel in a dose-dependent manner. Our results suggest that Loureirin B inhibits Ca2+ influx and IL-2 secretion in Jurkat T cells by inhibiting both KV1.3 and STIM1/Orai1 channels. These studies also revealed an additional molecular target for Loureirin B-induced immunosuppressive effect, which makes it a promising leading compound for treating autoimmune diseases.
Highlights
Loureirin B (LrB) is a Resina Draconis (RD)-derived flavonoid and a traditional Chinese medicine bearing multifaceted effects on numerous diseases (Fan et al, 2014; Bai et al, 2015)
We used Jurkat T cell as a T cell model and applied CRISPR/Cas9 system to KO KV1.3 to study the effects of LrB on Ca2+ influx and cytokine release in the absence of KV1.3
We found that KO KV1.3 reduced IL-2 secretion and Ca2+ influx after T cell activation, it did not abolish the inhibitory effect of LrB on IL-2 secretion and Ca2+ influx
Summary
Loureirin B (LrB) is a Resina Draconis (RD)-derived flavonoid and a traditional Chinese medicine bearing multifaceted effects on numerous diseases (Fan et al, 2014; Bai et al, 2015). LrB was reported to be a plasminogen activator inhibitor-1 (PAI-1) that promoted blood circulation and reduced the size of arterial thrombus (Jiang et al, 2017). LrB alone or combined with other RD constituents inhibited voltage-gated sodium (NaV) channel, transient receptor potential vanilloid 1 channel, and acid-sensing ion channel in dorsal root ganglion (DRG) neurons and ameliorated inflammatory pain (Chen et al, 2018; Wan et al, 2019). LrB and RD possess promising immunosuppressive effects. A recent study showed that LrB could reduce the severity of inflammation in Crohn’s disease via inhibiting the expression levels of inflammatory cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis
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