Interferon-gamma acts proapoptotic on hepatic stellate cells (HSC) and abrogates the antiapoptotic effect of interferon-alpha by an HSP70-dependant pathway.
The activated hepatic stellate cell (HSC) is an important fibrogenic cell type of the liver. Interferon-alpha (IFN-alpha) has recently been shown to elicit an antiapoptotic effect on activated HSC by a JAK-2-dependent inhibition of caspase-8 activation. As JAK-2 has so far been shown to be a member of the IFN-gamma signal transduction pathway we studied the effect of IFN-gamma on apoptosis as well as on its signaling in primary cultured rat HSC. IFN-gamma elicited a proapoptotic effect in activated HSC. The combination of both, IFN-gamma and IFN-alpha, however, completely cancelled each other's effect. No effect of the two cytokines on major members of apoptosis-regulating systems (CD95, CD95L, bcl-2, bax, bcl-xL, p53, p21WAF1, p27, NFkappaB) could be observed. Western Blot analysis revealed that gene expression of the chaperone HSP70 was found to be downregulated by IFN-gamma but upregulated by IFN-alpha. The effect could be abrogated by administration of both. After transfection of activated HSC with a pCMV-HSP70 M expression vector the proapoptotic effect of IFN-gamma was cancelled. Using HSP70 antisense, the antiapoptotic effect of IFN-alpha was cancelled as well. However IFN-gamma had no effect on upregulation of JAK-2 and pJAK-2 by IFN-alpha. Taken together IFN-gamma and IFN-alpha exert opposite effects on apoptosis in HSC. This effect is mediated by their counteracting effect on HSP70 expression which acts antiapoptotic at the level of caspase-8.
Saile
Bernhard
B
University of Göttingen, Department of Internal Medicine, Section of Gastroenterology and Endocrinology, Göttingen, Germany.
Eisenbach
Christoph
C
Dudas
Jozsef
J
El-Armouche
Hammoudeh
H
Ramadori
Giuliano
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D018840:HSP70 Heat-Shock Proteins; D016898:Interferon-alpha; D018832:Molecular Chaperones; D007371:Interferon-gamma; D020169:Caspases