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首页> 外文期刊>The journal of clinical investigation >IL-36 γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes
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IL-36 γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes

机译：IL-36 <粗体>γ驱动EGFR / MEK抑制和共谋<斜杆菌痤疮的皮肤毒性

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摘要

Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/MEKi) are beneficial for the treatment of solid cancers but are frequently associated with severe therapy-limiting acneiform skin toxicities. The underlying molecular mechanisms are poorly understood. Using gene expression profiling we identified IL-36γ and IL-8 as candidate drivers of EGFRi/MEKi skin toxicity. We provide molecular and translational evidence that EGFRi/MEKi in concert with the skin commensal bacterium Cutibacterium acnes act synergistically to induce IL-36γ in keratinocytes and subsequently IL-8, leading to cutaneous neutrophilia. IL-36γ expression was the combined result of C . acnes –induced NF-κB activation and EGFRi/MEKi–mediated expression of the transcription factor Krüppel-like factor 4 (KLF4), due to the presence of both NF-κB and KLF4 binding sites in the human IL-36γ gene promoter. EGFRi/MEKi increased KLF4 expression by blockade of the EGFR/MEK/ERK pathway. These results provide an insight into understanding the pathological mechanism of the acneiform skin toxicities induced by EGFRi/MEKi and identify IL-36γ and the transcription factor KLF4 as potential therapeutic targets.
机译：表皮生长因子受体（EGFR）和MEK抑制剂（EGFRI / MEKI）有益于治疗固体癌症，但经常与严重治疗限制痤疮皮肤毒性相关。潜在的分子机制明显很差。使用基因表达分析我们将IL-36γ和IL-8鉴定为EGFRI / MEKI皮肤毒性的候选司机。我们提供分子和翻译证据，即Egri / Meki与皮肤共生细菌的Cencibacterium Acnes协同作用，以诱导角质形成细胞中的IL-36γ，随后IL-8导致皮肤中性粒细胞。 IL-36γ表达是C的总结结果。由于人IL-36γ基因启动子中的NF-κB和KLF4结合位点，痤疮诱导的NF-κB活化和EGFRI / MEKI介导的转录因子Krüppel样因子4（KLF4）的表达。 EGFI / MEKI通过封锁EGFR / MEK / ERK路径增加了KLF4表达。这些结果提供了了解EGFRI / MEKI诱导的痤疮皮肤毒性的病理机制，并鉴定IL-36γ和转录因子KLF4作为潜在治疗靶标的病理机制。

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