Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
Department of Pediatrics, National Jewish Health, Denver, Colorado, USA; Department of Pediatrics, University of Colorado Denver, Aurora, Colorado, USA.
J Invest Dermatol. 2021 Apr;141(4):770-778. doi: 10.1016/j.jid.2020.09.009. Epub 2020 Oct 7.
Atopic Dermatitis is an inflammatory skin disease associated with broad defects in skin barrier function caused by increased levels of type-2 cytokines (IL-4 and IL-13) that repress keratinocyte (KC) differentiation. Although crucial in mediating allergic disease, the mechanisms for gene repression induced by type-2 cytokines remain unclear. In this study, we determined that gene repression requires the master regulator of the epidermal differentiation program, p63. We found that type-2 cytokine-mediated inhibition of the expression of genes involved in early KC differentiation, including keratin 1, keratin 10, and DSC-1, is reversed by p63 blockade. Type-2 cytokines, through p63, also regulate additional genes involved in KC differentiation, including CHAC-1, STC2, and CALML5. The regulation of the expression of these genes is ablated by p63 small interfering RNA as well. In addition, we found that IL-4 and IL-13 and Staphylococcus aureus lipoteichoic acid work in combination through p63 to further suppress the early KC differentiation program. Finally, we found that IL-4 and IL-13 also inhibit the activity of Notch, a transcription factor required to induce early KC differentiation. In conclusion, type-2 cytokine-mediated gene repression and blockade of KC differentiation are multifactorial, involving pathways that converge on transcription factors critical for epidermal development, p63 and Notch.
特应性皮炎是一种炎症性皮肤病，与皮肤屏障功能广泛缺陷有关，这种缺陷是由 2 型细胞因子（IL-4 和 IL-13）水平升高引起的，它们抑制角质形成细胞（KC）分化。虽然 2 型细胞因子在介导过敏疾病中至关重要，但它们诱导基因抑制的机制仍不清楚。在这项研究中，我们确定基因抑制需要表皮分化程序的主调控因子 p63。我们发现，2 型细胞因子介导的早期 KC 分化相关基因表达的抑制，包括角蛋白 1、角蛋白 10 和 DSC-1，可被 p63 阻断所逆转。2 型细胞因子通过 p63 还调节 KC 分化的其他基因，包括 CHAC-1、STC2 和 CALML5。这些基因的表达也可被 p63 小干扰 RNA 消除。此外，我们发现 IL-4 和 IL-13 以及金黄色葡萄球菌脂磷壁酸通过 p63 协同作用，进一步抑制早期 KC 分化程序。最后，我们发现 IL-4 和 IL-13 也抑制 Notch 的活性，而 Notch 是诱导早期 KC 分化所必需的转录因子。总之，2 型细胞因子介导的基因抑制和 KC 分化的阻断是多因素的，涉及到与表皮发育的关键转录因子（p63 和 Notch）相关的途径。
