In situ expression of transforming growth factor-beta1-3, latent transforming growth factor-beta binding protein and tumor necrosis factor-alpha in liver tissue from patients with chronic hepatitis C.
BACKGROUND
The mechanisms determining liver damage in chronic hepatitis C remain unclear. The aim was to evaluate the in situ expression of transforming growth factor beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha), two key cytokines implicated as important pathogenic mediators in the development of liver fibrosis.


METHODS
In situ expression of TNF-alpha and of TGF-beta isoforms 1-3, and its transport protein latent TGF-beta binding protein (LTBP), was determined by immunohistochemistry in 9 untreated patients with chronic hepatitis C infection and in 6 controls without liver disease. In addition, TGF-beta1 expression was analyzed in 10 HCV patients before and after treatment with interferon-alpha alone, or in combination with ribavirin.


RESULTS
Liver biopsies from HCV patients showed positive staining for TGF-beta1-3 isoforms and LTBP, and to a lesser degree for TNF-alpha, in areas with inflammation and fibrosis. Normal control liver showed no positive staining. TGF-beta1 expression before treatment, quantified by morphometric analysis, did not differ between non-responders and sustained responders. In patients responding to therapy, TGF-beta1 expression decreased in parallel with histological improvement, while no difference in TGF-beta1 expression was seen before and after treatment in non-responders.


CONCLUSIONS
These results suggest that TNF-alpha and all three isoforms of TGF-beta are involved in the pathogenesis of HCV related liver disease, and that treatment leading to eradication of the virus affects the expression of TGF-beta1.
Kinnman
N
N
Dept of Gastroenterology, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden.
Andersson
U
U
Hultcrantz
R
R
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D001706:Biopsy; D002352:Carrier Proteins / Q000378:metabolism*; D005260:Female; D006526:Hepatitis C / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007372:Interferons / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms; D012367:RNA, Viral / Q000097:blood; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000998:Antiviral Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D020033:Protein Isoforms; D012367:RNA, Viral; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D014409:Tumor Necrosis Factor-alpha; D007372:Interferons