Exocrine pancreatic disorders in transsgenic mice expressing human keratin8

Kerarins K8 and K18 are the major components of the intermediate-filament c ytoskeleton of simple epithelia. Increased levels of these keratins have be en correlated with various tumor cell characteristics, including progressio n to malignancy, invasive behavior, and drug sensitivity, although a role f or K8/K18 in tumorigenesis has not yet been demonstrated. To examine the fu nction of these keratins, we generated mice expressing the human K8 (hk8) g ene, which leads to a moderate keratin-content increase in their simple epi thelia. These mice displayed progressive exocrine pancreas alterations, inc luding dysplasia and loss of acinar architecture, redifferentiation of acin ar to ductal cells, inflammation, fibrosis, and substitution of exocrine by adipose tissue, as well as increased cell proliferation and apoptosis. His tological changes were not observed in other simple epithelia, such as the Liver. Electron microscopy showed that transgenic acinar cells have keratin s organized in abundant filament bundles dispersed throughout the cytoplasm , in contrast to control acinar cells, which have scarce and apically conce ntrated filaments. The phenotype found was very similar to that reported fo r transgenic mice expressing a dominant-negative mutant TGF-beta type II re ceptor (TGF beta RII mice). We show that these TGF beta RII mutant mice als o have elevated K8/K18 levels. These results indicate that simple epithelia l keratins play a relevant role in the regulation of exocrine pancreas home ostasis and support the idea that disruption of mechanisms that normally re gulate keratin expression in vivo could be related to inflammatory and neop lastic pancreatic disorders.