Interferon Alfa Down–Regulates Collagen Gene Transcription and Suppresses Experimental Hepatic Fibrosis in Mice

Abstract

The equilibrium between the production and degradation of collagen is rigorously controlled by a number of growth factors and cytokines. Interferon alfa (IFN-alpha) is now widely used for the treatment of chronic hepatitis C, which can improve serum levels of fibrotic markers and the degree of hepatic fibrosis, not only in patients who responded to therapy but also in those in whom it is ineffective. These findings may suggest that IFN-alpha possesses direct antifibrotic effects in addition to its antiviral activity. However, in contrast to IFN-gamma, which has been shown to suppress collagen gene transcription, little is known about the mechanisms responsible for the antifibrotic effects of IFN-alpha. Here, we report that IFN-alpha, when administered into transgenic mice harboring the alpha2(I) collagen gene (COL1A2) promoter sequence, significantly repressed promoter activation and prevented the progression of hepatic fibrosis induced by carbon tetrachloride injection. Transient transfection assays indicated that IFN-alpha decreased the steady-state levels of COL1A2 messenger RNA (mRNA) and inhibited basal and TGF-beta/Smad3-stimulated COL1A2 transcription in activated hepatic stellate cells (HSC). These inhibitory effects of IFN-alpha on COL1A2 transcription were exerted through the interaction between phosphorylated Stat1 and p300. Blocking of the IFN-alpha signal by overexpressing the intracellular domain-deleted IFN receptor increased basal COL1A2 transcription and abolished the inhibitory effects of IFN-alpha. In conclusion, our results indicate that IFN-alpha antagonizes the TGF-beta/Smad3-stimulated COL1A2 transcription in vitro and suppresses COL1A2 promoter activation in vivo, providing a molecular basis for antifibrotic effects of IFN-alpha.

A Novel Small Compound That Promotes Nuclear Translocation of YB-1 Ameliorates Experimental Hepatic Fibrosis in Mice

“…The antifibrotic potential of HSc025 was further evaluated by histological examination. Consistent with a previous study (19), progressive hepatic fibrosis was induced by repeated CCl 4 injections (Fig. 5E, Control).…”

“…Hepatic fibrosis was induced in C57BL/6 mice by intraperitoneal injections of 0.1 ml/kg body weight of CCl 4 twice a week for 8 weeks as described previously (19). The mice were treated with either 3, 15, and 75 mg/kg/day of HSc025 or vehicle for 4 weeks after injections of carbon tetrachloride for 4 weeks.…”

Interferon augments the anti-fibrotic activity of an angiotensin-converting enzyme inhibitor in patients with refractory chronic hepatitis C

“…It has been reported that IFN significantly suppressed the HSC, and it also inhibited the promoter activity of pro-collagen gene [7] . However, in the clinical practice, fibrosis improvement with IFNbased therapy could be observed only in the virological responders [6] .…”

“…However, the histological improvement of liver fibrosis could be observed only in the SVR patients [6] . It has been reported that IFN inhibited the collagen promoter activity in the activated hepatic stellate cells (HSC), which play a pivotal role in liver fibrosis development [7] . Furthermore, it is well…”

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

“…IFN-α and IFN-γ markedly decreases HSC activation and collagen synthesis (177,218) and attenuates ECM deposition in experimental liver fibrosis (219)(220)(221). Studies in patients with chronic hepatitis C suggest that IFN-α may inhibit the progression of liver fibrosis irrespective of virological response (222,223).…”