Translocation of p21(Cip1/WAF1) from the nucleus to the cytoplasm correlates with pancreatic myofibroblast to fibroblast cell conversion.
OBJECTIVE
In the pancreas, myofibroblasts (MFBs) were shown to play an important role in the cellular response during inflammation and injury. However, there is only fragmentary information concerning the fate of these cells in pancreas regeneration and fibrosis development.


METHODS
Explant cultures of rat pancreatic tissue were used as a model to follow cellular dynamics and phenotype conversion of pancreatic MFBs in vitro. For detailed biochemical analyses a pancreatic fibroblast cell line (long culture fibroblast (LCF)) was generated from MFBs in a long term culture. Cerulein induced acute pancreatitis and dibutyltin dichloride induced pancreas fibrosis were used as experimental models for acute and chronic fibrogenic reactions, respectively.


RESULTS
In the explant culture, pancreatic MFBs which derived from fat storing fibroblastic cells underwent apoptosis or converted again to fibroblasts. The phenotype switch to fibroblasts was associated with translocation of p21(Cip1/WAF1) from the nucleus into the cytoplasm. Molecular analyses in LCFs revealed subsequent binding to and inhibition of the activities of Rho kinase 2 and apoptosis signal regulating kinase 1. In the experimentally established pancreas fibrosis, fibroblasts with cytoplasmic expression of p21(Cip1/WAF1) were distributed throughout fibrotic bands whereas in experimental acute pancreatitis MFBs with nuclear expression of p21(Cip1/WAF1) dominated.


CONCLUSIONS
The results indicate that pancreatic MFBs are transient and suggest that intracellular localisation of p21(Cip1/WAF1) can contribute to the phenotype conversion of these cells to fibroblasts in culture and experimental injury.
Manapov
F
F
Department of Internal Medicine, University of Rostock, Ernst-Heydemann-Str 6, 18055 Rostock, Germany.
Muller
P
P
Rychly
J
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003593:Cytoplasm / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010195:Pancreatitis / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C493958:Cdkn1a protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018994:Myosin Light Chains; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases