CXCR2 agonists in ADPKD liver cyst fluids promote cell proliferation.
Autosomal dominant polycystic kidney disease (ADPKD) is a highly prevalent genetic disease that results in cyst formation in kidney and liver. Cytokines and growth factors secreted by the cyst-lining epithelia are positioned to initiate autocrine/paracrine signaling and promote cyst growth. Comparative analyses of human kidney and liver cyst fluids revealed disparate cytokine/growth factor profiles. CXCR2 agonists, including IL-8, epithelial neutrophil-activating peptide (ENA-78), growth-related oncogene-alpha (GRO-alpha), are potent proliferative agents that were found at high levels in liver but not kidney cyst fluids. Liver cysts are lined by epithelial cells derived from the intrahepatic bile duct (i.e., cholangiocytes). In polarized pkd2(WS25/-) mouse liver cyst epithelial monolayers, CXCR2 agonists were released both apically and basally, indicating that they may act both on the endothelial and epithelial cells within or lining the cyst wall. IL-8 and human liver cyst fluid induced cell proliferation of HMEC-1 cells, a human microvascular endothelial cell line, and Mz-ChA1 cells, a human cholangiocyte cell model. IL-8 expression can be regulated by specific stresses. Hypoxia and mechanical stretch, two likely stressors acting on the liver cyst epithelia, significantly increased IL-8 secretion and promoter activity. AP-1, c/EBP, and NF-kappaB were required but not sufficient to drive the stress-induced increase in IL-8 transcription. An upstream element between -272 and -1,481 bp allowed for the stress-induced increase in IL-8 transcription. These studies support the hypothesis that CXCR2 signaling promotes ADPKD liver cyst growth.
Amura
Claudia R
CR
Division of Gastroenterology, Department of Medicine, University of Colorado Health Sciences Center, Box B-146, Denver, CO 80262, USA.
Brodsky
Kelley S
KS
Gitomer
Berenice
B
McFann
Kim
K
Lazennec
Gwendal
G
Nichols
Matthew T
MT
Jani
Alkesh
A
Schrier
Robert W
RW
Doctor
R Brian
RB
D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D016764:Cell Polarity; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism; D054365:Chemokine CXCL5 / Q000378:metabolism; D020420:Cyst Fluid / Q000378:metabolism*; D003560:Cysts / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D023063:Receptors, Interleukin-8B / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013314:Stress, Mechanical; D050396:TRPP Cation Channels / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D016209:Interleukin-8; D023063:Receptors, Interleukin-8B; D050396:TRPP Cation Channels