title: Activation of the IGF1 system characterizes cholangiocyte survival during progression of primary biliary cirrhosis.
abstract: 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.
authors.affiliation: Department of Experimental Medicine, University of L'Aquila, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Anna Rosa
authors.initials: AR
authors.lastname: Floreani
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Mancino
authors.forename: Antonio
authors.initials: A
authors.lastname: Franchitto
authors.forename: Maria
authors.initials: M
authors.lastname: Guido
authors.forename: Guido
authors.initials: G
authors.lastname: Carpino
authors.forename: Adriano
authors.initials: A
authors.lastname: De Santis
authors.forename: Mario
authors.initials: M
authors.lastname: Angelico
authors.forename: Adolfo F
authors.initials: AF
authors.lastname: Attili
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
mesh_terms: D017209:Apoptosis; D001652:Bile Ducts / Q000737:chemistry* / Q000166:cytology; D002470:Cell Survival; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051028:bcl-2-Associated X Protein / Q000032:analysis
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt