Interferon-γ-induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG-CoA reductase.,FEBS Open Bio

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Interferon-γ-induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG-CoA reductase.
FEBS Open Bio ( IF 2.8 ) Pub Date : 2020-04-15 , DOI: 10.1002/2211-5463.12854
Akihiro Maenaka _{1,

2} , Iwasaki Kenta ₃ , Akinobu Ota ₄ , Yuko Miwa ₃ , Wataru Ohashi ₅ , Kosei Horimi ₂ , Yutaka Matsuoka ₂ , Masafumi Ohnishi ₁ , Kazuharu Uchida ₃ , Takaaki Kobayashi ₂

Affiliation

In organ transplantation, donor‐specific HLA antibody (DSA) is considered a major cause of graft rejection. Because DSA targets primarily donor‐specific human leukocyte antigen (HLA) expressed on graft endothelial cells, the prevention of its expression is a possible strategy for avoiding or salvaging DSA‐mediated graft rejection. We examined the effect of various clinically used drugs on HLA class II expression on endothelial cells. Interferon‐γ (IFN‐γ)‐induced HLA class II DR (HLA‐DR) was downregulated by everolimus (EVR, 49.1% ± 0.8%; P < 0.01) and fluvastatin (FLU, 33.8% ± 0.6%; P < 0.01). Moreover, the combination of EVR and FLU showed a greater suppressive effect on HLA‐DR expression. In contrast, cyclosporine, tacrolimus, mycophenolic acid, and prednisolone did not exhibit any significant suppressive effect. FLU, but not EVR, suppressed mRNA of HLA‐DR. Imaging analysis revealed that HLA‐DR expressed in cytosol or on the cell surface was repressed by EVR (cytosol: 58.6% ± 4.9%, P < 0.01; cell surface: 80.9% ± 4.0%, P < 0.01) and FLU (cytosol: 19.0% ± 3.4%, P < 0.01; cell surface: 48.3% ± 4.8%, P < 0.01). These data indicated that FLU and EVR suppressed IFN‐γ‐induced HLA‐DR expression at the transcriptional and post‐translational level, respectively, suggesting a potential approach for alleviating DSA‐related issues in organ transplantation.

中文翻译：

干扰素-γ诱导的内皮细胞HLA II类表达通过抑制mTOR和HMG-CoA还原酶而降低。

在器官移植中，供体特异性HLA抗体（DSA）被认为是移植排斥的主要原因。因为DSA主要靶向在移植内皮细胞上表达的供体特异性人类白细胞抗原（HLA），所以防止其表达是避免或挽救DSA介导的移植排斥的一种可能策略。我们检查了各种临床使用的药物对内皮细胞上HLA II类表达的影响。依维莫司（EVR，49.1％±0.8％; P <0.01）和氟伐他汀（FLU，33.8％±0.6％; P）下调干扰素-γ（IFN-γ）诱导的HLA II类DR（HLA-DR） <0.01）。此外，EVR和FLU的组合对HLA-DR表达具有更大的抑制作用。相反，环孢菌素，他克莫司，麦考酚酸和泼尼松龙没有显示出明显的抑制作用。FLU而非EVR抑制HLA-DR的mRNA。影像学分析显示，EVR（胞浆：58.6％±4.9％，P <0.01;细胞表面：80.9％±4.0％，P <0.01）和FLU（胞浆： 19.0％±3.4％，P <0.01;细胞表面：48.3％±4.8％，P <0.01）。这些数据表明FLU和EVR分别在转录和翻译后水平上抑制IFN-γ诱导的HLA-DR表达，这表明缓解器官移植中DSA相关问题的潜在方法。

更新日期：2020-04-15

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