Aim: Acute rejection is still a major problem in transplantation and one of the most important causes of late graft loss. Cyclosporine and tacrolimus are widely used for suppression of T cell function to avoid graft rejection, but long-term use of these compounds is associated with serious toxicities. Quercetin, a flavonoid found in fruits and vegetables, has been demonstrated to exhibit cytoprotective effects through the induction of heme oxygenase (HO) -1, an enzyme involved in heme catabolism. We hypothesized that quercetin induces HO-1 in T cells and suppresses T cell function via HO-1. In the present study, we showed that quercetin suppressed the A23187-mediated expression of interleukin (IL) -2 in T cells.Methods: Mouse splenocytes, enriched T cells, and EL4 cells, a mouse T cell line, were treated with quercetin, and then stimulated with A23187, a calcium ionophore, concanavalin A, or anti-CD3ε and anti-CD28 antibodies. Cell proliferation, expression of IL-2, calcium mobilization, apoptosis, cell cycle, and phosphorylation of extracellular signal-regulated kinase (ERK) were investigated.Results: Quercetin induced HO-1, and this induction of HO-1 was implicated in the suppression of IL-2 production. Furthermore, the induction of HO-1 by quercetin suppressed the influx of calcium ions, a known trigger of IL-2 production. Additionally, quercetin suppressed T cell proliferation through promotion of cell cycle arrest via HO-1 induction, but quercetin did not induce apoptosis. To investigate the role of the signal transduction pathway in quercetin's effect on cell proliferation, we evaluated the phosphorylation of ERK in T cells. Quercetin suppressed the A23187-mediated stimulation of ERK, an effect that was mediated through HO-1. These results suggested that HO-1 is involved in the suppressive effects of quercetin on T cell activation and proliferation.Conclusion: Our findings indicate that the quercetin may be a promising candidate for inducing HO-1 in T cells, thereby facilitating immunosuppressive effects.

中文翻译：

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血红素加氧酶-1参与槲皮素抑制T细胞活化。

目的：急性排斥反应仍然是移植中的主要问题，并且是造成移植后期丢失的最重要原因之一。环孢霉素和他克莫司广泛用于抑制T细胞功能以避免移植排斥，但长期使用这些化合物会产生严重的毒性。槲皮素是一种在水果和蔬菜中发现的类黄酮，已被证明通过诱导血红素加氧酶（HO）-1（一种参与血红素分解代谢的酶）表现出细胞保护作用。我们假设槲皮素在T细胞中诱导HO-1，并通过HO-1抑制T细胞功能。在本研究中，我们显示槲皮素抑制T细胞中A23187介导的白介素（IL）-2的表达。方法：用槲皮素处理小鼠脾细胞，富集的T细胞和小鼠T细胞系EL4细胞，然后用A23187，钙离子载体，伴刀豆球蛋白A或抗CD3ε和抗CD28抗体刺激。研究了槲皮素诱导的HO-1的表达，并推测其与HO-1的诱导有关。抑制IL-2产生。此外，槲皮素对HO-1的诱导可抑制钙离子的流入，钙离子是IL-2产生的已知触发因素。另外，槲皮素通过HO-1诱导促进细胞周期停滞，从而抑制了T细胞增殖，但槲皮素未诱导凋亡。为了研究信号转导途径在槲皮素对细胞增殖的影响中的作用，我们评估了T细胞中ERK的磷酸化。槲皮素抑制了A23187介导的ERK刺激，这一作用是通过HO-1介导的。这些结果表明HO-1参与了槲皮素对T细胞活化和增殖的抑制作用。结论：我们的研究结果表明，槲皮素可能是诱导T细胞中HO-1的有前途的候选者，从而促进了免疫抑制作用。