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.
Molecular Alcohol Research in Gastroenterology, Department of Medicine II, Faculty of Medicine at Mannheim, University of Heidelberg, Germany. honglei.weng@medma.uni-heidelberg.de
Hong-Lei
HL
Weng
Yan
Y
Liu
Jia-Lin
JL
Chen
Tong
T
Huang
Li-Jun
LJ
Xu
Patricio
P
Godoy
Jun-Hua
JH
Hu
Cheng
C
Zhou
Felix
F
Stickel
Alexander
A
Marx
Rainer M
RM
Bohle
Vincent
V
Zimmer
Frank
F
Lammert
Sebastian
S
Mueller
Michelle
M
Gigou
Didier
D
Samuel
Peter R
PR
Mertens
Manfred V
MV
Singer
Helmut K
HK
Seitz
Steven
S
Dooley
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