1. ¹Section of Anatomic Pathology, Department of Oncological and Surgical Science, University of Padova, Padova, Italy
2. ²Section of Internal Medicine, Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy
3. ³Section of Gastroenterology, Department of Surgical Science and Gastroenterology, University of Verona, Verona, Italy
4. ⁴Istituto di Ricerca S De Bellis, Castellana Grotte, Italy
5. ⁵Department of Gastroenterology, Ospedale Regionale, Bolzano, Italy
6. ⁶Section of Anatomic Pathology, Department of Pathology, University of Verona, Verona, Italy

Correspondence: Dr G Fattovich, MD, Servizio Gastroenterologia, Dipartimento Scienze Chirurgiche e Gastroenterologiche, Università di Verona, Policlinico GB Rossi, P.le LA Scuro, 10, 37134 Verona, Italy. E-mail: giovanna_fattovich@tin.it

^*These two authors have contributed equally to this paper.

Received 9 August 2005; Revised 10 January 2006; Accepted 20 February 2006; Published online 12 May 2006.

Abstract

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-B) (a transcription factor coordinating the expression of stress genes involved in immune response and inflammation), of the polypeptide transforming growth factor beta-1 (TGF-1) 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-1, 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-1, TIMP-1, MMP-2, and MMP-9 were evaluated by enzyme-linked immunosorbent assay. Liver expression of muscle-specific -actin, NF-B, TGF-1, 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- and NF-B 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-B 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--1 and NF-B and favors metalloproteinase activity, and may thereby modulate hepatic fibrogenetic events.