Large induction of keratinocyte growth factor expression by serum growth factors and pro-inflammatory cytokines in cultured fibroblasts.

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.