Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan.
Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan.
J Invest Dermatol. 2021 Nov;141(11):2646-2655.e6. doi: 10.1016/j.jid.2021.04.002. Epub 2021 Apr 16.
IL-33 is a chromatin-associated multifunctional cytokine implicated in the pathogenesis of atopic dermatitis (AD), an inflammatory skin disorder characterized by skin barrier dysfunction. The previous reports show that IL-33 is highly detected in the nucleus of epidermal keratinocytes in AD lesions compared with that in unaffected or normal skin. However, it is unclear whether intracellular IL-33 directly contributes to the pathogenesis of AD. T helper type 2 cytokines IL-4 and IL-13 that are elevated in AD lesions suppress keratinocyte differentiation to impair skin barrier function. We investigated whether intracellular IL-33 is involved in IL-4 and IL-13 function. In monolayer culture and living skin equivalent analyses, IL-4 and IL-13 increased the expression of full-length IL-33 in the nucleus of keratinocytes by activating the MAPK/extracellular signal‒regulated kinase kinase/extracellular signal‒regulated kinase signaling pathway, which is necessary for the inhibition of differentiation markers FLG, LOR, keratin 1, and keratin 10. The nuclear IL-33 functions as a transcription cofactor of signal transducer and activator of transcription 3, increasing the binding of phosphorylated signal transducer and activator of transcription 3 to FLG promoter, thereby inhibiting its transcription, and it inhibits the expression of transcription factor RUNX1 by signal transducer and activator of transcription 3 and signal transducer and activator of transcription 6, thereby downregulating LOR, keratin 1, and keratin 10. Thus, the elevated nuclear IL-33 in the epidermis of AD lesions may be involved in the pathogenesis of AD by inhibiting keratinocyte differentiation and skin barrier function.
白细胞介素 33 是一种染色质相关的多功能细胞因子，与特应性皮炎（AD）的发病机制有关，AD 是一种炎症性皮肤病，其特征是皮肤屏障功能障碍。先前的报告表明，与未受影响或正常皮肤相比，AD 病变表皮角质形成细胞的细胞核中高度检测到白细胞介素 33。然而，尚不清楚细胞内白细胞介素 33 是否直接参与 AD 的发病机制。AD 病变中升高的辅助性 T 细胞 2 型细胞因子白细胞介素 4 和白细胞介素 13 抑制角质形成细胞分化，损害皮肤屏障功能。我们研究了细胞内白细胞介素 33 是否参与白细胞介素 4 和白细胞介素 13 的功能。在单层培养和活体皮肤等效物分析中，白细胞介素 4 和白细胞介素 13 通过激活丝裂原活化蛋白激酶/细胞外信号调节激酶激酶/细胞外信号调节激酶信号通路，增加细胞核中全长白细胞介素 33 的表达，这对于抑制分化标志物 FLG、LOR、角蛋白 1 和角蛋白 10 是必要的。核内白细胞介素 33 作为信号转导和转录激活因子 3 的转录共激活因子，增加磷酸化信号转导和转录激活因子 3 与 FLG 启动子的结合，从而抑制其转录，并通过信号转导和转录激活因子 3 和信号转导和转录激活因子 6 抑制转录因子 RUNX1 的表达，从而下调 LOR、角蛋白 1 和角蛋白 10。因此，AD 病变表皮中升高的核内白细胞介素 33 可能通过抑制角质形成细胞分化和皮肤屏障功能参与 AD 的发病机制。
