Institute of Dermatology, Guangzhou Medical University, Guangzhou, People's Republic of China; Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou, People's Republic of China.
Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
J Invest Dermatol. 2019 Feb;139(2):400-411. doi: 10.1016/j.jid.2018.07.032. Epub 2018 Aug 29.
The roles of IL-22 in the pathomechanisms of psoriasis have been well demonstrated. Gap junctional intercellular communication (GJIC) is widely known for its involvement in multiple biological and pathological processes such as growth-related events, cell differentiation, and inflammation. Here, we show that IL-22 significantly decreased GJIC and down-regulated Cx43 expression in HaCaT cells. Cx43 overexpression markedly inhibited the proliferation of and increased GJIC in HaCaT cells, but the silencing of Cx43 exerted the opposite effects. Additionally, Cx43 overexpression effectively rescued the IL-22-induced decrease in GJIC in HaCaT cells. The IL-22-induced down-regulation of Cx43 expression and decrease in GJIC can be significantly blocked by the JNK inhibitor SP600125 and by the overexpression of IL-22RA2 (which specifically binds to IL-22 and inhibits its activity), but not by the NF-κB inhibitor BAY11-7082, in HaCaT cells. Furthermore, the IL-22-induced down-regulation of Cx43 expression mediated by the JNK signaling pathway was confirmed in a mouse model of IL-22-induced psoriasis-like dermatitis. Similarly, Cx43 expression was significantly lower in the lesional skin than in the nonlesional skin of patients with psoriasis. These results suggest that IL-22 decreases GJIC by activating the JNK signaling pathway, which down-regulates Cx43 expression; this process is a possible pathomechanism of keratinocyte hyperproliferation in psoriasis.
IL-22 在银屑病的发病机制中的作用已得到充分证实。缝隙连接细胞间通讯（GJIC）广泛参与多种生物学和病理学过程，如生长相关事件、细胞分化和炎症。在这里，我们表明 IL-22 可显著降低 HaCaT 细胞中的 GJIC 并下调 Cx43 表达。Cx43 过表达显著抑制 HaCaT 细胞的增殖并增加 GJIC，但 Cx43 沉默则产生相反的效果。此外，Cx43 过表达可有效挽救 IL-22 诱导的 HaCaT 细胞中 GJIC 的降低。IL-22 诱导的 Cx43 表达下调和 GJIC 降低可被 JNK 抑制剂 SP600125 和 IL-22RA2 的过表达（其特异性结合 IL-22 并抑制其活性）显著阻断，但不能被 NF-κB 抑制剂 BAY11-7082 阻断，在 HaCaT 细胞中。此外，在 IL-22 诱导的银屑病样皮炎的小鼠模型中证实了 JNK 信号通路介导的 IL-22 诱导的 Cx43 表达下调。同样，在银屑病患者的皮损皮肤中 Cx43 表达明显低于非皮损皮肤。这些结果表明，IL-22 通过激活 JNK 信号通路降低 GJIC，从而下调 Cx43 表达；这一过程可能是银屑病角质形成细胞过度增殖的发病机制之一。
