Effects of interferon plus ribavirin treatment on NF-κB, TGF-β1, and metalloproteinase activity in chronic hepatitis C

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-jB) (a transcription factor coordinating the expression of stress genes involved in immune response and inflammation), of the polypeptide transforming growth factor beta-1 (TGF-b1) 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-b1, 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-b1, TIMP-1, MMP-2, and MMP-9 were evaluated by enzyme-linked immunosorbent assay. Liver expression of muscle-specific a-actin, NF-jB, TGF-b1, 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-b and NF-jB 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-jB 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-b-1 and NF-jB and favors metalloproteinase activity, and may thereby modulate hepatic fibrogenetic events.

TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer

“…This study elucidates a mechanism through which the highest levels of PD-1 are induced. Indeed, high TGF-β1 serum levels are associated with worse disease outcome in HCV infection (66) and TGF-β1 expression is high in the tumor microenvironment of advanced stages of cancer, which may further limit the efficacy of T cells against disease in those settings (67-69). Given the potential for autoimmunity with PD-1 therapy, it is worth investigating whether inhibitors of Smad3 used in combination with other immunotherapeutic agents activate T cells expressing the highest levels of PD-1 rather than all T cells bearing PD-1.…”

Beneficial drugs for liver diseases

“…Interestingly, in patients who are non-responders to IFN-α 2b , given as an antiviral agent, improve or stabilizes fibrosis (Mukherjee and Lyden, 2006). Combination therapy with interferon and ribavirin affects the tissue expression of TGF-β 1 and NF-κB, favors metalloproteinase activity, and thereby modulates hepatic fibrogenic events (Guido et al, 2006). It has also been suggested that by the antifibrotic properties of interferons in humans, this compound may ameliorate portal hypertension (Rincon et al, 2006).…”

Expression of MMPs and TIMPs in liver fibrosis – a systematic review with special emphasis on anti-fibrotic strategies

“…flCollagenase activity (therapeutic exp.) › Body weight, serum albumin and total protein › Guido et al[127] IFN-a + ribavirin In vivo chronic HCV in humans MMP-1 staining › Fibrosis fl 2 [II, IV] (continued on next page)…”