Department of Dermatology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China.
Department of Dermatology, University of California San Diego, La Jolla, CA, 92093, USA.
Br J Dermatol. 2021 Dec;185(6):1200-1208. doi: 10.1111/bjd.20594. Epub 2021 Aug 17.
Glucocorticoids (GCs) are generally envisioned as immunosuppressive, but in conditions such as rosacea and perioral dermatitis they can lead to increased skin inflammation. In lung epithelia, GCs promote expression of the proinflammatory cytokine CCL20, which contributes to steroid-resistant asthma. In the skin, CCL20 stimulates inflammation by recruiting T helper 17 T lymphocytes and dendritic cells, and is elevated in papulopustular rosacea.
To understand if, and how, GCs affect CCL20 expression in human keratinocytes. CCL20 expression was assessed by quantitative reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay.
Selective inhibition of candidate genes and signalling pathways was performed using RNA interference and chemical inhibitors. The binding of activated GC receptor to genomic DNA was determined by chromatin immunoprecipitation, and enhancer activity of genomic sequences was measured with a reporter assay.
We found that GC treatment increased CCL20 expression in human keratinocytes and murine skin, both in the undisturbed state and with tumour necrosis factor-α stimulation. GC repressed proinflammatory signalling pathways, including nuclear factor kappa B and p38/mitogen-activated protein kinase, but these inhibitory effects were opposed by the direct binding of activated GC receptor to the CCL20 enhancer, promoting CCL20 expression.
Viewed together, these findings demonstrate a mechanism by which GCs induce expression of CCL20 in keratinocytes, which may contribute to the inflammation seen in steroid-exacerbated skin conditions.
糖皮质激素（GCs）通常被认为具有免疫抑制作用，但在酒渣鼻和口周皮炎等情况下，它们会导致皮肤炎症增加。在肺上皮细胞中，GC 促进促炎细胞因子 CCL20 的表达，这有助于类固醇抵抗性哮喘。在皮肤中，CCL20 通过招募辅助性 T 细胞 17（Th17）T 淋巴细胞和树突状细胞来刺激炎症，并且在脓疱性酒渣鼻中升高。
了解 GC 是否以及如何影响人角质形成细胞中 CCL20 的表达。通过定量逆转录聚合酶链反应和酶联免疫吸附试验评估 CCL20 的表达。
使用 RNA 干扰和化学抑制剂对候选基因和信号通路进行选择性抑制。通过染色质免疫沉淀测定激活的 GC 受体与基因组 DNA 的结合，并用报告基因测定测量基因组序列的增强子活性。
我们发现 GC 处理可增加人角质形成细胞和小鼠皮肤中 CCL20 的表达，无论是在未受干扰的状态下还是在肿瘤坏死因子-α刺激下。GC 抑制了促炎信号通路，包括核因子 kappa B 和 p38/丝裂原活化蛋白激酶，但这些抑制作用被激活的 GC 受体与 CCL20 增强子的直接结合所拮抗，从而促进 CCL20 的表达。
综上所述，这些发现表明 GC 诱导角质形成细胞中 CCL20 表达的机制，这可能有助于类固醇加重的皮肤疾病中观察到的炎症。
