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Activation of the IGF1 System Characterizes Cholangiocyte Survival During Progression of Primary Biliary Cirrhosis

Paolo Onori¹, Domenico Alvaro¹, AnnaRosa Floreani, MariaGrazia Mancino, Antonio Franchitto, Maria Guido, Guido Carpino, Adriano De Santis, Mario Angelico, Adolfo F. Attili and Eugenio Gaudio

Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy (PO); Department of Clinical Medicine, Division of Gastroenterology (DA,MGM,ADS,AFA), Department of Anatomy (AF,GC,EG), University of Rome, La Sapienza, Rome, Italy; Department of Surgical and Gastroenterological Sciences, University of Padua, Padua, Italy (ARF,MG); Gastroenterology Unit, University "Tor Vergata", Rome, Italy (MA); and University of Rome, La Sapienza, Polo Pontino, Latina, Italy (DA)

Correspondence to: Domenico Alvaro, MD, Division of Gastroenterology, Department of Clinical Medicine, via R. Rossellini 51, 00137 Rome, Italy. E-mail: domenico.alvaro{at}uniroma1.it

We evaluated the IGF1 system in cholangiocytes of primay biliary cirrhosis (PBC) patients and investigated the relationships with apoptosis. Biopsies of PBC patients (n=32) and normal subjects (n=5) were investigated by immunohistochemistry for expression in cholangiocytes of IGF1, IGF1-R, pAKT, terminal deoxynucleotide transferase end labeling (TUNEL), Bax (proapoptotic protein), and Bcl2 (antiapoptotic protein). Whereas normal cholangiocytes were almost negative, cholangiocytes of PBC patients showed strong IHC staining for IGF1, IGF1-R, and pAKT, which increases from stage I to stage IV, where >70% of cholangiocytes were positive. Bax/Bcl2 ratio reached the highest value (4.6) in PBC stage III when apoptosis is maximal (24% TUNEL positivity), whereas it declines in stage IV (1.4) when only 7.8% cholangiocytes were TUNEL positive. In PBC stages III and IV, expression of IGF1, IGF1-R, and pAKT in cholangiocytes was directly correlated with the antiapoptotic Bcl2 and inversely correlated with proapoptotic Bax, Bax/Bcl2 ratio, and TUNEL positivity. In conclusion, cholangiocytes of PBC patients showed a marked increase in IGF1, IGF1-R, and pAKT expression involving most cholangiocytes surviving in the terminal ductopenic stage. This was associated and correlated with a balance of pro- and antiapoptotic proteins favoring survival rather than apoptosis, suggesting a major role of IGF1 system in promoting cholangiocyte survival. (J Histochem Cytochem 55:327–334, 2007)

Key Words: primary biliary cirrhosis • IGF1 • cholangiocytes • apoptosis • cholestasis

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