ABSTRACT: BACKGROUND: Hepatitis C Virus (HCV), a single stranded RNA virus, affects
millions of people worldwide and leads to chronic infection characterized by chronic
inflammation in the liver and in peripheral immune cells. Chronic liver inflammation
leads to progressive liver damage. MicroRNAs (miRNA) regulate inflammation (miR-155,
-146a and -125b) as well as hepatocyte function (miR-122). METHODS: Here we hypothesized
that microRNAs are dysregulated in chronic HCV infection. We examined miRNAs in the
circulation and in peripheral monocytes of patients with chronic HCV infection to
evaluate if specific miRNA expression correlated with HCV infection. RESULTS: We found
that monocytes from chronic HCV infected treatment-naive (cHCV) but not treatment
responder patients showed increased expression of miR-155, a positive regulator of
TNFalpha, and had increased TNFalpha production compared to monocytes of normal controls.
After LPS stimulation, miR-155 levels were higher in monocytes from cHCV patients
compared to controls. MiR-125b, which has negative regulatory effects on inflammation,
was decreased in cHCV monocytes compared to controls. Stimulation of normal monocytes
with TLR4 and TLR8 ligands or HCV core, NS3 and NS5 recombinant proteins induced a
robust increase in both miR-155 expression and TNFalpha production identifying potential
mechanisms for in vivo induction of miR-155. Furthermore, we found increased serum
miR-155 levels in HCV patients compared to controls. Serum miR-125b and miR-146a levels
were also increased in HCV patients. Serum levels of miR-122 were elevated in cHCV
patients and correlated with increased ALT and AST levels and serum miR-155 levels.
CONCLUSION: In conclusion, our novel data demonstrate that miR-155, a positive regulator
of inflammation, is upregulated both in monocytes and in the serum of patients with
chronic HCV infection. Our study suggests that HCV core, NS3, and NS5 proteins or
TLR4 and TLR8 ligands can mediate increased miR-155 and TNFalpha production in chronic
HCV infection. The positive correlation between serum miR-155 and miR-122 increase
in cHCV may be an indicator of inflammation-induced hepatocyte damage.
