TY - JOUR
T1 - Secretion of cytokines and growth factors into autosomal dominant polycystic kidney disease liver cyst fluid
AU - Nichols, Matthew T.
AU - Gidey, Elsa
AU - Matzakos, Tom
AU - Dahl, Rolf
AU - Stiegmann, Greg
AU - Shah, Raj J.
AU - Grantham, Jared J.
AU - Fitz, J. Gregory
AU - Doctor, R. Brian
PY - 2004/10
Y1 - 2004/10
N2 - The principal extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD) involves formation of liver cysts derived from intrahepatic bile ducts. Autocrine and paracrine factors secreted into the cyst would be positioned to modulate the rate of hepatic cyst growth. The aim of this study was to identify potential growth factors present in human ADPKD liver cyst fluid. Cytokine array and enzyme-linked immunosorbent assay analysis of human ADPKD liver cyst fluid detected epithelial neutrophil attractant 78, interleukin (IL)-6 (503 ± 121 pg/mL); and IL-8 (4,488 ± 355 pg/mL); and elevated levels of vascular endothelial growth factor compared with non-ADPKD bile (849 ± 144 pg/mL vs. 270 pglmL maximum concentration). ADPKD liver cyst cell cultures also released IL-8 and vascular endothelial growth factor, suggesting that cystic epithelial cells themselves are capable of secreting these factors. Western blotting of cultured cyst cells and immunostaining of intact cysts demonstrate that cysteine-X-cysteine receptor 2, an epithelial neutrophil attractant 78 and IL-8 receptor, is expressed at the apical domain of cyst lining epithelial cells. Suggesting the cystic epithelial cells may exist in hypoxic conditions, electron microscopy of the ADPKD liver cyst epithelium revealed morphological features similar to those observed in ischemic bile ducts. These features include elongation, altered structure, and diminished abundance of apical microvilli. In conclusion, IL-8, epithelial neutrophil attractant 78, IL-6, and vascular endothelial growth factor may serve as autocrine and paracrine factors to direct errant growth of ADPKD liver cyst epithelia. Interruption of these signaling pathways may provide therapeutic targets for inhibiting liver cyst expansion.
AB - The principal extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD) involves formation of liver cysts derived from intrahepatic bile ducts. Autocrine and paracrine factors secreted into the cyst would be positioned to modulate the rate of hepatic cyst growth. The aim of this study was to identify potential growth factors present in human ADPKD liver cyst fluid. Cytokine array and enzyme-linked immunosorbent assay analysis of human ADPKD liver cyst fluid detected epithelial neutrophil attractant 78, interleukin (IL)-6 (503 ± 121 pg/mL); and IL-8 (4,488 ± 355 pg/mL); and elevated levels of vascular endothelial growth factor compared with non-ADPKD bile (849 ± 144 pg/mL vs. 270 pglmL maximum concentration). ADPKD liver cyst cell cultures also released IL-8 and vascular endothelial growth factor, suggesting that cystic epithelial cells themselves are capable of secreting these factors. Western blotting of cultured cyst cells and immunostaining of intact cysts demonstrate that cysteine-X-cysteine receptor 2, an epithelial neutrophil attractant 78 and IL-8 receptor, is expressed at the apical domain of cyst lining epithelial cells. Suggesting the cystic epithelial cells may exist in hypoxic conditions, electron microscopy of the ADPKD liver cyst epithelium revealed morphological features similar to those observed in ischemic bile ducts. These features include elongation, altered structure, and diminished abundance of apical microvilli. In conclusion, IL-8, epithelial neutrophil attractant 78, IL-6, and vascular endothelial growth factor may serve as autocrine and paracrine factors to direct errant growth of ADPKD liver cyst epithelia. Interruption of these signaling pathways may provide therapeutic targets for inhibiting liver cyst expansion.
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U2 - 10.1002/hep.1840400413
DO - 10.1002/hep.1840400413
M3 - Article
C2 - 15382115
AN - SCOPUS:4644353372
SN - 0270-9139
VL - 40
SP - 836
EP - 846
JO - Hepatology
JF - Hepatology
IS - 4
ER -