Interleukin‐4 induces human hepatocyte apoptosis through a Fas‐independent pathway

IL‐4 is overexpressed in liver grafts during severe recurrent hepatitis C and rejection. Hepatocyte apoptosis is involved in both these phenomena. We therefore examined the proapoptotic effect of IL‐4 on HepG2 cells and human hepatocytes in vitro, together with the underlying mechanisms. We first measured IL‐4 receptor expression, STAT6 activation by IL‐4, and STAT6 inhibition by an anti‐IL‐4 antibody or by STAT6 siRNA transfection. We then focused on the pathways involved in IL‐4‐mediated apoptosis and the role of STAT6 activation in apoptosis initiation. The IL‐4 receptor was expressed on both cell types, and STAT6 was activated by IL‐4. Both anti‐IL‐4 and STAT‐6 siRNA inhibited this activation. IL‐4 induced apoptosis of both HepG2 cells (P= 0.008 vs. untreated control) and human hepatocytes (P<0.001 vs. untreated control). IL‐4 reduced the mitochondrial membrane potential, activated Bid and Bax, and augmented caspase 3, 8, and 9 activity. STAT6 blockade inhibited IL‐4‐induced apoptosis. Expression of Fas and Fas ligand was unaffected when HepG2 cells and hepatocytes were cultured with IL‐4, and Fas/FasL pathway blockade failed to inhibit IL‐4‐induced apoptosis. These results show that IL‐4 induces apoptosis of human hepatocytes through IL‐4 receptor binding, STAT6 activation, decreased mitochondrial membrane potential, and increased caspase activation, independently of the Fas pathway. IL‐4 might thus contribute to the progression of severe liver graft damage.—Aoudjehane, L., Podevin, P., Scatton, O., Jaffray, P., Dusanter‐Fourt, I., Feldmann, G., Massault, P. P., Grira, L., Bringuier, A., Dousset, B., Chouzenoux, S., Soubrane, O., Calmus, Y., Conti, F. Interleukin‐4 induces human hepatocyte apoptosis through a Fas‐independent pathway. FASEB J. 21, 1433–1444 (2007)