Differential regulation of keratinocyte growth factor and hepatocyte growth factor/scatter factor by different cytokines in human corneal and limbal fibroblasts.

Abstract

Corneal epithelial stem cells and transient amplifying cells are located in the limbal and corneal regions, respectively. In a serum-free medium with or without different cytokines, limbal fibroblasts consistently produced greater levels of keratinocyte growth factor (KGF) transcript and protein than corneal fibroblasts, whereas corneal fibroblasts produced greater levels of hepatocyte growth factor/ scatter factor (HGF/SF) transcript and protein than limbal fibroblasts. Expression of HGF/SF transcript and protein was up-regulated mildly by epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), or platelet-derived growth factor B (PDGF-BB) but markedly by interleukin-1 beta (IL-1 beta) and was more pronounced in limbal than in corneal fibroblasts. Expression of KGF transcript was down-regulated by EGF, TGF-alpha, and PDGF-BB, was markedly up-regulated by IL-1 beta, and was more pronounced in limbal than in corneal fibroblasts. Expression of KGF protein was up-regulated markedly by IL-1 beta and moderately by PDGF-BB, especially in limbal fibroblasts. TGF-beta 1 uniquely turned off transcript and protein expression of HGF/SF and KGF in corneal fibroblasts. Although its transcript levels were similarly down-regulated in limbal fibroblasts, KGF protein levels were paradoxically up-regulated by TGF-beta 1 when added alone or with TGF-alpha or IL-1 beta. These data indicate that KGF and HGF/SF, two fibroblast-derived epithelial mitogens, are expressed differentially by limbal and corneal fibroblasts and are modulated by cytokines activated during epithelial-mesenchymal interactions, suggesting that they may play a different role in modulating corneal epithelial stem cells and transient amplifying cells.