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Originally published online as doi:10.2353/ajpath.2008.070830 on March 18, 2008

Published online before print March 18, 2008
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(American Journal of Pathology. 2008;172:882-892.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070830

Keratin Overexpression Levels Correlate with the Extent of Spontaneous Pancreatic Injury

Diana M. Toivola*, Ikuo Nakamichi*, Pavel Strnad*, Sara A. Michie{dagger}, Nafisa Ghori{ddagger}, Masaru Harada, Karin Zeh§, Robert G. Oshima, Helene Baribault|| and M. Bishr Omary*

From the Departments of Medicine,* Pathology,{dagger} and Microbiology and Immunology,{ddagger} Veteran’s Administration Palo Alto Health Care System and Stanford University Digestive Disease Center, Palo Alto; SGX Pharmaceuticals, Inc.,§ San Diego; The Burnham Institute, La Jolla; and Amgen,|| South San Francisco, California

Correspondence: Address correspondence to Diana Toivola, Abo Akademi University, Dept of Biology, Tykistokatu 6, FIN-20521, Turku, Finland. E-mail: dtoivola{at}abo.fi

Mutation of the adult hepatocyte keratins K8 and K18 predisposes to liver disease. In contrast, exocrine pancreas K8 and K18 are dispensable and are co-expressed with limited levels of membrane-proximal K19 and K20. Overexpression of mutant K18 or genetic ablation of K8 in mouse pancreas is well tolerated whereas overexpression of K8 causes spontaneous chronic pancreatitis. To better understand the effect of exocrine pancreatic keratin overexpression, we compared transgenic mice that overexpress K18, K8, or K8/K18, associated with minimal, modest, or large increases in keratin expression, respectively, with nontransgenic wild-type (WT) mice. Overexpression of the type-II keratin K8 up-regulated type-I keratins K18, K19, and K20 and generated K19/K20-containing neocytoplasmic typical or short filaments; however, overexpression of K18 had no effect on K8 levels. K8- and K18-overexpressing pancreata were histologically similar to WT, whereas K8/K18 pancreata displayed age-enhanced vacuolization and atrophy of the exocrine pancreas and exhibited keratin hyperphosphorylation. Zymogen granules in K8/K18 pancreata were 50% smaller and more dispersed than their normal apical concentration but were twice as numerous as in WT controls. Therefore, modest keratin overexpression has minor effects on the exocrine pancreas whereas significant keratin overexpression alters zymogen granule organization and causes aging-associated exocrine atrophy. Keratin absence or mutation is well tolerated after pancreatic but not liver injury, whereas excessive overexpression is toxic to the pancreas but not the liver when induced under basal conditions.






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Copyright © 2008 by the American Society for Investigative Pathology.