Florin Lore, Knebel Julia, Zigrino Paola, Vonderstrass Birgitta, Mauch Cornelia, Schorpp-Kistner Marina, Szabowski Axel, Angel Peter
Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
J Invest Dermatol. 2006 Apr;126(4):902-11. doi: 10.1038/sj.jid.5700123.
The cutaneous response to injury and stress comprises a temporary change in the balance between epidermal proliferation and differentiation as well as an activation of the immune system. Soluble factors play an important role in the regulation of these complex processes by coordinating the intercellular communication between keratinocytes, fibroblasts, and inflammatory cells. In this study, we demonstrate that JunB, a member of the activator protein-1 transcription factor family, is an important regulator of cytokine expression and thus critically involved in the cutaneous response to injury and stress. Mice lacking JunB in the skin develop normally, indicating that JunB is neither required for cutaneous organogenesis, nor homeostasis. However, upon wounding and treatment with the phorbol ester 12-O-decanoyl-phorbol-13-acetate, JunB-deficiency in the skin likewise resulted in pronounced epidermal hyperproliferation, disturbed differentiation, and prolonged inflammation. Furthermore, delayed tissue remodelling was observed during wound healing. These phenotypic skin abnormalities were associated with JunB-dependent alterations in expression levels and kinetics of important mediators of wound repair, such as granulocyte macrophage colony-stimulating factor, growth-regulated protein-1, macrophage inflammatory protein-2, and lipocalin-2 in both the dermal and epidermal compartment of the skin, and a reduced ability of wound contraction of mutant dermal fibroblasts in vitro.
皮肤对损伤和应激的反应包括表皮增殖与分化平衡的暂时改变以及免疫系统的激活。可溶性因子通过协调角质形成细胞、成纤维细胞和炎症细胞之间的细胞间通讯，在这些复杂过程的调节中发挥重要作用。在本研究中，我们证明激活蛋白-1转录因子家族成员JunB是细胞因子表达的重要调节因子，因此在皮肤对损伤和应激的反应中起关键作用。皮肤中缺乏JunB的小鼠发育正常，这表明JunB对于皮肤器官发生和稳态均非必需。然而，在受伤并用佛波酯12-O-十四酰佛波醇-13-乙酸酯处理后，皮肤中JunB的缺乏同样导致明显的表皮过度增殖、分化紊乱和炎症延长。此外，在伤口愈合过程中观察到组织重塑延迟。这些皮肤表型异常与伤口修复重要介质（如粒细胞巨噬细胞集落刺激因子、生长调节蛋白-1、巨噬细胞炎症蛋白-2和脂钙蛋白-2）在皮肤真皮和表皮层的表达水平和动力学的JunB依赖性改变有关，并且突变真皮成纤维细胞在体外的伤口收缩能力降低。
