During the inflammatory process,
hepcidin overexpression favours the development of anaemia of
chronic diseases which represents the second most common form of anaemia worldwide. The identification of therapeutic agents decreasing
hepcidin expression is therefore an important goal. The aim of this study was to target the STAT3 signalling involved in the development of increased
hepcidin expression related to chronic
inflammation. In a co-culture model associating mouse hepatocytes and rat liver epithelial cells, the
mRNA levels of hepcidin1,
albumin,
aldolase B,
Cyp3a4, Stat3, Smad4 and
iron regulatory genes were measured by real-time PCR. STAT3 and phosphorylated SMAD1/5/8
proteins were analysed by Western blot. At variance of hepatocyte pure culture, co-culture provided high levels of hepcidin1
mRNA, reaching 400% of the freshly isolated hepatocyte values after 6 days of culture.
Hepcidin expression was associated with the maintenance of hepatocyte phenotype, STAT3 phosphorylation and functional BMP/SMAD pathway. Stat3 siRNAs inhibited the hepcidin1
mRNA expression. STAT3 inhibitors, including
curcumin,
AG490 and a
peptide (PpYLKTK), reduced hepcidin1
mRNA expression even when cells were additionally exposed to
IL-6. Hepcidin1
mRNA was expressed at high levels by hepatocytes in the co-culture model, and STAT3 pathway activation was controlled through STAT3 inhibitors. Such inhibitors could be useful to prevent anaemia related to
hepcidin overexpression during chronic
inflammation.