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- Title
Interleukin-4 induces human hepatocyte apoptosis through a Fas-independent pathway.
- Authors
Aoudjehane, Lynda; Podevin, Philippe; Scatton, Olivier; Jaffray, Patrick; Dusanter-Fourt, Isabelle; Feldmann, Gérard; Massault, Pierre-Philippe; Grira, Lilia; Bringuier, Annie; Dousset, Bertrand; Chouzenoux, Sandrine; Soubrane, Olivier; Calmus, Yvon; Conti, Filomena
- Abstract
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.
- Subjects
INTERLEUKIN-4; LIVER cells; APOPTOSIS; LIVER transplantation; HEPATITIS C
- Publication
FASEB Journal, 2007, Vol 21, Issue 7, p1433
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.06-6319com