Activation of the IGF1 system characterizes cholangiocyte survival during progression of primary biliary cirrhosis.
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.
Onori
Paolo
P
Department of Experimental Medicine, University of L'Aquila, Italy.
Alvaro
Domenico
D
Floreani
Anna Rosa
AR
Mancino
Maria Grazia
MG
Franchitto
Antonio
A
Guido
Maria
M
Carpino
Guido
G
De Santis
Adriano
A
Angelico
Mario
M
Attili
Adolfo F
AF
Gaudio
Eugenio
E
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
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