The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis.
It is unknown whether transforming growth factor beta1 (TGF-beta1) signaling uniformly participates in fibrogenic chronic liver diseases, irrespective of the underlying origin, or if other cytokines such as interleukin (IL)-13 share in fibrogenesis (e.g., due to regulatory effects on type I pro-collagen expression). TGF-beta1 signaling events were scored in 396 liver tissue samples from patients with diverse chronic liver diseases, including hepatitis B virus (HBV), hepatitis C virus (HCV), Schistosoma japonicum infection, and steatosis/steatohepatitis. Phospho-Smad2 staining correlated significantly with fibrotic stage in patients with HBV infection (n = 112, P < 0.001) and steatosis/steatohepatitis (n = 120, P < 0.01), but not in patients with HCV infection (n = 77, P > 0.05). In tissue with HBx protein expression, phospho-Smad2 was detectable, suggesting a functional link between viral protein expression and TGF-beta1 signaling. For IL-13, immunostaining correlated with fibrotic stage in patients with HCV infection and steatosis/steatohepatitis. IL-13 protein was more abundant in liver tissue lysates from three HCV patients compared with controls, as were IL-13 serum levels in 68 patients with chronic HCV infection compared with 20 healthy volunteers (72.87 +/- 26.38 versus 45.41 +/- 3.73, P < 0.001). Immunohistochemistry results suggest that IL-13-mediated liver fibrogenesis may take place in the absence of phospho-signal transducer and activator of transcription protein 6 signaling. In a subgroup of patients with advanced liver fibrosis (stage > or =3), neither TGF-beta nor IL-13 signaling was detectable.


CONCLUSIONS
Depending on the cause of liver damage, a predominance of TGF-beta or IL-13 signaling is found. TGF-beta1 predominance is detected in HBV-related liver fibrogenesis and IL-13 predominance in chronic HCV infection. In some instances, the underlying fibrogenic mediator remains enigmatic.
Weng
Hong-Lei
HL
Molecular Alcohol Research in Gastroenterology, Department of Medicine II, Faculty of Medicine at Mannheim, University of Heidelberg, Germany. honglei.weng@medma.uni-heidelberg.de
Liu
Yan
Y
Chen
Jia-Lin
JL
Huang
Tong
T
Xu
Li-Jun
LJ
Godoy
Patricio
P
Hu
Jun-Hua
JH
Zhou
Cheng
C
Stickel
Felix
F
Marx
Alexander
A
Bohle
Rainer M
RM
Zimmer
Vincent
V
Lammert
Frank
F
Mueller
Sebastian
S
Gigou
Michelle
M
Samuel
Didier
D
Mertens
Peter R
PR
Singer
Manfred V
MV
Seitz
Helmut K
HK
Dooley
Steven
S
D006801:Humans; D066298:In Vitro Techniques; D018793:Interleukin-13 / Q000502:physiology*; D008103:Liver Cirrhosis / Q000209:etiology*; D008107:Liver Diseases / Q000209:etiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
D018793:Interleukin-13; D053773:Transforming Growth Factor beta1