Glioblastoma multiforme (GBM) is a primary brain tumor characterized by extensive necrosis and immunosuppressive inflammation. The mechanisms by which this inflammation develops and persists in GBM remain elusive. We identified two cytokines interleukin-1β (IL-1) and oncostatin M (OSM) that strongly negatively correlate with patient survival. We found that these cytokines activate RelB/p50 complexes by a canonical NF-κB pathway, which surprisingly drives expression of proinflammatory cytokines in GBM cells, but leads to their inhibition in non-transformed astrocytes. We discovered that one allele of the gene encoding deacetylase Sirtuin 1 (SIRT1), needed for repression of cytokine genes, is deleted in 80% of GBM tumors. Furthermore, RelB specifically interacts with a transcription factor Yin Yang 1 (YY1) in GBM cells and activates GBM-specific gene expression programs. As a result, GBM cells continuously secrete proinflammatory cytokines and factors attracting/activating glioma-associated microglia/macrophages and thus, promote a feedforward inflammatory loop.

中文翻译：

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RelB充当驱动多形性胶质母细胞瘤中慢性炎症的分子开关。

多形胶质母细胞瘤（GBM）是一种原发性脑部肿瘤，其特征在于广泛的坏死和免疫抑制性炎症。这种炎症在GBM中发展并持续的机制仍然难以捉摸。我们确定了两种细胞因子白介素-1β（IL-1）和制瘤素M（OSM）与患者的生存密切相关。我们发现这些细胞因子通过典型的NF-κB途径激活RelB / p50复合物，该途径出乎意料地驱动了GBM细胞中促炎细胞因子的表达，但导致了它们在未转化的星形胶质细胞中的抑制作用。我们发现抑制细胞因子基因所需的编码脱乙酰基酶Sirtuin 1（SIRT1）的基因的一个等位基因在80％的GBM肿瘤中缺失。此外，RelB与GBM细胞中的转录因子Yin Yang 1（YY1）特异性相互作用，并激活GBM特异性基因表达程序。结果，GBM细胞连续分泌促炎细胞因子和吸引/激活胶质瘤相关小胶质细胞/巨噬细胞的因子，从而促进前馈性炎症循环。