Unresolved inflammation maintained by release of danger‐associated molecular patterns, particularly high‐mobility group box‐1 (HMGB1), is crucial for hepatocellular carcinoma (HCC) pathogenesis. To further characterize interactions between leucocytes and necrotic cancerous tissue, a cellular model of necroinflammation was studied in which murine Raw 264.7 macrophages or primary splenocytes were exposed to necrotic lysates (N‐lys) of murine hepatoma cells or primary hepatocytes. In comparison to those derived from primary hepatocytes, N‐lys from hepatoma cells were highly active—inducing in macrophages efficient expression of inflammatory cytokines like C‐X‐C motif ligand‐2 , tumor necrosis factor‐α, interleukin (IL)‐6 and IL‐23‐p19. This activity associated with higher levels of HMGB1 in hepatoma cells and was curbed by pharmacological blockage of the receptor for advanced glycation end product (RAGE)/HMGB1 axis or the mitogen‐activated protein kinases ERK1/2 pathway. Analysis of murine splenocytes furthermore demonstrated that N‐lys did not comprise of functionally relevant amounts of TLR4 agonists. Finally, N‐lys derived from hepatoma cells supported inflammatory splenic Th17 and Th1 polarization as detected by IL‐17, IL‐22 or interferon‐γ production. Altogether, a straightforward applicable model was established which allows for biochemical characterization of immunoregulation by HCC necrosis in cell culture. Data presented indicate a remarkably inflammatory capacity of necrotic hepatoma cells that, at least partly, depends on the RAGE/HMGB1 axis and may shape immunological properties of the HCC microenvironment.

中文翻译：

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鼠坏死性炎症细胞模型显示RAGE依赖的细胞因子诱导与肝癌细胞损伤相关。

通过释放与危险相关的分子模式，尤其是高迁移率族box-1（HMGB1），维持未解决的炎症对于肝细胞癌（HCC）发病机理至关重要。为了进一步表征白细胞与坏死癌组织之间的相互作用，研究了一种坏死性炎症细胞模型，其中将鼠Raw 264.7巨噬细胞或原代脾细胞暴露于鼠肝癌细胞或原代肝细胞的坏死裂解液（N-lys）中。与源自原代肝细胞的细胞相比，来自肝癌细胞的N-lys具有高活性-诱导巨噬细胞有效表达炎症细胞因子，如C-X-C基序配体-2，肿瘤坏死因子-α，白介素（IL）-6和IL-23-p19。这种活性与肝癌细胞中HMGB1的较高水平有关，并被晚期糖基化终产物（RAGE）/ HMGB1轴或促分裂原激活的蛋白激酶ERK1 / 2途径的药理作用所抑制。对鼠脾细胞的分析还表明，Nlys不包含功能相关量的TLR4激动剂。最后，IL-17，IL-22或干扰素-γ产生可检测到肝细胞来源的N-lys支持炎性脾脏Th17和Th1极化。总共建立了一个简单的适用模型，该模型允许通过HCC坏死在细胞培养物中对免疫调节进行生化表征。所提供的数据表明坏死性肝癌细胞具有明显的发炎能力，至少部分地，