Interferon gamma (IFN-γ) induces an endothelial proimmunogenic phenotype through the JAK/STAT1 pathway, which can shape the activation of alloreactive leukocytes in transplant rejection. In immune cells, the DNA-binding protein B cell lymphoma 6 (BCL6) controls the transcription of inflammatory genes. This study tested if BCL6 modulates IFN-γ-induced gene expression in endothelial cells. In vitro, BCL6 was IFN-γ-inducible in primary human endothelium, along with CXCR3 chemokines and human leukocyte antigen (HLA). BCL6, HLA II, and CXCL9 were also increased in human cardiac transplants during acute rejection. Knockdown of BCL6 augmented, whereas overexpression and BTB domain inhibitors (BCL6-BTBi) suppressed, HLA II and CXCR3 chemokine expression but not HLA I. Further, BCL6 had a greater effect on HLA-DR and DP but was less involved in regulating HLA-DQ expression. The effect correlated with BCL6 binding motifs in or near affected genes. The BCL6 DNA recognition sequence was highly similar to that of STAT1, and BTBi reduced STAT1’s transcriptional activity in vitro. Our results show for the first time that BCL6 selectively controls IFN-γ-induced endothelial gene expression, advancing our understanding of the endogenous mechanisms regulating donor immunogenicity.

中文翻译：

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转录抑制因子 B 细胞淋巴瘤 6 调节内皮细胞中 CXCR3 趋化因子和人类白细胞抗原 II 的表达


干扰素 γ （IFN-γ） 通过 JAK/STAT1 通路诱导内皮促免疫原性表型，这可以塑造移植排斥反应中同种异体反应性白细胞的激活。在免疫细胞中，DNA 结合蛋白 B 细胞淋巴瘤 6 （BCL6） 控制炎症基因的转录。本研究测试了 BCL6 是否调节 IFN γ诱导的内皮细胞基因表达。在体外，BCL6 与 CXCR3 趋化因子和人白细胞抗原 （HLA） 一起在原代人内皮中是 IFN γ诱导的。在急性排斥反应期间，人心脏移植中的 BCL6 、 HLA II 和 CXCL9 也增加。BCL6 的敲除增强，而过表达和 BTB 结构域抑制剂 （BCL6-BTBi） 抑制，HLA II 和 CXCR3 趋化因子表达，但 HLA I 不表达。此外，BCL6 对 HLA-DR 和 DP 的影响更大，但对调节 HLA-DQ 表达的参与较少。该效应与受影响基因中或附近的 BCL6 结合基序相关。BCL6 DNA 识别序列与 STAT1 高度相似，BTBi 在体外降低了 STAT1 的转录活性。我们的结果首次表明 BCL6 选择性控制 IFN γ诱导的内皮基因表达，促进了我们对调节供体免疫原性的内源性机制的理解。