Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Kanagawa, Japan.
PLoS One. 2012;7(7):e40343. doi: 10.1371/journal.pone.0040343. Epub 2012 Jul 5.
Homeostatic regulation of epidermal keratinocytes is controlled by the local cytokine milieu. However, a role for suppressor of cytokine signaling (SOCS), a negative feedback regulator of cytokine networks, in skin homeostasis remains unclear. Keratinocyte specific deletion of Socs3 (Socs3 cKO) caused severe skin inflammation with hyper-production of IgE, epidermal hyperplasia, and S100A8/9 expression, although Socs1 deletion caused no inflammation. The inflamed skin showed constitutive STAT3 activation and up-regulation of IL-6 and IL-20 receptor (IL-20R) related cytokines, IL-19, IL-20 and IL-24. Disease development was rescued by deletion of the Il6 gene, but not by the deletion of Il23, Il4r, or Rag1 genes. The expression of IL-6 in Socs3 cKO keratinocytes increased expression of IL-20R-related cytokines that further facilitated STAT3 hyperactivation, epidermal hyperplasia and neutrophilia. These results demonstrate that skin homeostasis is strictly regulated by the IL-6-STAT3-SOCS3 axis. Moreover, the SOCS3-mediated negative feedback loop in keratinocytes has a critical mechanistic role in the prevention of skin inflammation caused by hyperactivation of STAT3.
表皮角质形成细胞的动态平衡调节受局部细胞因子微环境的控制。然而，抑制细胞因子信号（SOCS）在皮肤稳态中的作用仍然不清楚，SOCS 是细胞因子网络的负反馈调节剂。角质形成细胞特异性敲除 Socs3（Socs3 cKO）导致严重的皮肤炎症，伴有 IgE 的过度产生、表皮增生和 S100A8/9 的表达，而 Socs1 缺失则不会引起炎症。炎症皮肤表现为 STAT3 的持续激活和与 IL-6 和 IL-20 受体（IL-20R）相关细胞因子的上调，包括 IL-19、IL-20 和 IL-24。IL-6 基因缺失可挽救疾病的发展，但缺失 Il23、Il4r 或 Rag1 基因则不能。Socs3 cKO 角质形成细胞中 IL-6 的表达增加了与 IL-20R 相关的细胞因子的表达，这进一步促进了 STAT3 的过度激活、表皮增生和中性粒细胞增多。这些结果表明，皮肤稳态受 IL-6-STAT3-SOCS3 轴的严格调节。此外，角质形成细胞中 SOCS3 介导的负反馈回路在预防由 STAT3 过度激活引起的皮肤炎症中具有关键的机制作用。
