Effects of interferon plus ribavirin treatment on NF-kappaB, TGF-beta1, and metalloproteinase activity in chronic hepatitis C.
Little is known about the cellular and molecular mechanisms underlying the effects of anti-viral therapy on the regression of liver inflammation and fibrosis in chronic hepatitis C. The aim of this study was to evaluate the effects of interferon alpha and ribavirin in combination therapy on the tissue expression of nuclear-factor kB (NF-kappaB) (a transcription factor coordinating the expression of stress genes involved in immune response and inflammation), of the polypeptide transforming growth factor beta-1 (TGF-beta1) and matrix metalloproteinases 1 (MMP-1) (both of which play an important part in the pathological process of liver fibrogenesis), and on the serum levels of soluble TGF-beta1, tissue inhibitors of metalloproteinases (TIMP)-1, and active endogenous MMP-2 and MMP-9 in paired (pre- and post-treatment) liver biopsy and serum samples of subjects with chronic hepatitis C. Serum levels of TGF-beta1, TIMP-1, MMP-2, and MMP-9 were evaluated by enzyme-linked immunosorbent assay. Liver expression of muscle-specific alpha-actin, NF-kappaB, TGF-beta1, and MMP-1 was studied immunohistochemically using commercially available mono- and polyclonal antisera in an avidin-biotin complex method. Combination therapy induced a reduction in the liver expression of TGF-beta and NF-kappaB and an increased expression of MMP-1, regardless of the virological response to the treatment. The greater expression of MMP-1 and lesser expression of NF-kappaB were both associated with an improvement in fibrosis score. These effects paralleled the significant increase in soluble MMP-9/TIMP-1 ratio in post-therapy sera. Combination therapy with interferon and ribavirin affects the tissue expression of TGF-beta-1 and NF-kappaB and favors metalloproteinase activity, and may thereby modulate hepatic fibrogenetic events.
Guido
Maria
M
Section of Anatomic Pathology, Department of Oncological and Surgical Science, University of Padova, Italy.
De Franceschi
Lucia
L
Olivari
Nicola
N
Leandro
Gioacchino
G
Felder
Martina
M
Corrocher
Roberto
R
Rugge
Massimo
M
Pasino
Michela
M
Lanza
Cristiano
C
Capelli
Paola
P
Fattovich
Giovanna
G
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D012189:Retrospective Studies; D012254:Ribavirin / Q000627:therapeutic use*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D016896:Treatment Outcome
D000998:Antiviral Agents; D015415:Biomarkers; D016898:Interferon-alpha; D016328:NF-kappa B; C508960:TGFB1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012254:Ribavirin; D045726:Metalloproteases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9