CXCR2 agonists in ADPKD liver cyst fluids promote cell proliferation

1 Division of Gastroenterology and 2 Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado; and 3 Institut National de la Santé et de la Recherche Médicale U844, Montpellier, France Submitted 2 October 2007 ; accepted in final form 10 January 2008 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- (GRO- ), 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- B 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. interleukin-8; cholangiocytes; endothelium; cytokines; growth factors; autosomal dominant polycystic kidney disease Address for reprint requests and other correspondence: R. B. Doctor, UCDHSC, Box B-146, 4200 East 9th Ave., Denver, CO 80262 (e-mail: brian.doctor{at}uchsc.edu )