Abstract
Sanguis draxonis (SD), also known as “Dragon’s Blood”, is a traditional herb medicine that has been used to treat a variety of complications with unknown mechanisms. Recent studies show that SD displays immunosuppressive activities and improves symptoms of type I diabetes in animal models. However, the mechanisms underlying SD’s immunosuppressive actions are not completely understood. The voltage-gated Kv1.3 channel plays a critical role in the pathogenesis of autoimmune diseases by regulating the functions of both T cells and B cells. Here we investigated the effect of SD and one of its active components loureirin B (LrB) on Kv1.3. Both SD and LrB inhibited Kv1.3-mediated currents, produced a membrane depolarization, and reduced Ca2+ influx in Jurkat T cells. In addition, application of LrB inhibited phytohemagglutinin (PHA)-induced IL-2 release from activated Jurkat T cells. Furthermore, point mutations in the selective filter region significantly reduced the inhibitory effect of LrB on Kv1.3. The results of these experiments provide evidence that LrB is a channel blocker of Kv1.3 by interacting with amino acid residues in its selective filter region. Direct inhibition of Kv1.3 in T cells by SD and LrB might be the cellular and molecular basis of SD-mediated immunosuppression.
Highlights
Plant-derived natural compounds play a critical role in ancient medicine [1] and become unique tools to dissect disease mechanisms as well as important reservoirs of potential new drugs [2,3,4,5]
Sanguis draxonis (SD) and loureirin B (LrB) inhibit Kv1.3 in Jurkat T cells Two major types of K+ channels are expressed by the human Jurkat T cells: the Kv1.3 [32], and the apamin-sensitive small conductance Ca2+-dependent K+ channel (SKCa2) which is activated by a rise in cytosolic Ca2+ [33]
Further studies using electrophysiological recordings have revealed that LrB, cochinchinenin A and cochinchinenin B are the three main active ingredients of SD and potentially mediate SD’s analgesic effect by inhibiting voltage-gated Na+ channels and the paininitiating TRPV1 channels in the primary sensory neurons [47,48,49,50]
Summary
Plant-derived natural compounds play a critical role in ancient medicine [1] and become unique tools to dissect disease mechanisms as well as important reservoirs of potential new drugs [2,3,4,5]. Further studies demonstrated that oral application of SD reduces release of inflammatory cytokines, protects pancreas function, and markedly improves diabetic symptoms in a rat model of streptozotocin (STZ)-induced Diabetes mellitus, a well-recognized autoimmune condition [10,11]. These studies have provided convincing evidence that SD is likely a potent inhibitor of autoimmune disorders, the cellular and molecular mechanisms underlying the immunomodulatory effect of SD are still poorly understood
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