Brauchle M, Angermeyer K, Hübner G, Werner S
Max-Planck-Institut für Biochemie, Abteilung Virusforschung, Martinsried, Germany.
Oncogene. 1994 Nov;9(11):3199-204.
We have recently demonstrated a large induction of keratinocyte growth factor expression in dermal fibroblasts during wound healing. To identify possible mediators of KGF induction, we have now analysed the regulation of KGF expression in vitro in cultured murine and human fibroblasts. Here we demonstrate that KGF mRNA and protein expression is low in quiescent fibroblasts but is strongly induced upon serum stimulation. This induction can be mediated by at least two different intracellular pathways involving protein kinase C or cAMP-dependent kinases. Our finding that induction of KGF expression by serum is independent of de novo protein synthesis demonstrates, that KGF is the product of a primary response gene. The stimulatory effect of serum on KGF expression is likely to be a combinatorial effect of different mitogens, since several purified serum growth factors also stimulated KGF expression but to a lesser extent compared to serum. Furthermore, we also found a strong KGF induction by interleukin-1 beta, tumor necrosis factor-alpha and interleukin-6, cytokines which are released by polymorphonuclear leukocytes and activated macrophages during wound healing. These data suggest that serum which is released upon hemorrhage as well as pro-inflammatory cytokines might be responsible for the KGF induction in vivo during skin repair.
我们最近证明，在伤口愈合过程中，真皮成纤维细胞中角质形成细胞生长因子（KGF）的表达大量增加。为了确定KGF诱导的可能介质，我们现在分析了培养的小鼠和人成纤维细胞中KGF表达的体外调控。在此我们证明，在静止的成纤维细胞中KGF mRNA和蛋白表达较低，但在血清刺激后会强烈诱导。这种诱导可由至少两条不同的涉及蛋白激酶C或cAMP依赖性激酶的细胞内途径介导。我们发现血清对KGF表达的诱导独立于从头合成蛋白质，这表明KGF是初级反应基因的产物。血清对KGF表达的刺激作用可能是不同促有丝分裂原的组合效应，因为几种纯化的血清生长因子也能刺激KGF表达，但与血清相比程度较小。此外，我们还发现白细胞介素-1β、肿瘤坏死因子-α和白细胞介素-6能强烈诱导KGF表达，这些细胞因子在伤口愈合过程中由多形核白细胞和活化的巨噬细胞释放。这些数据表明，出血时释放的血清以及促炎细胞因子可能是皮肤修复过程中体内KGF诱导的原因。
