TY - JOUR
T1 - IRF-1 is an essential mediator in IFN-γ-induced cell cycle arrest and apoptosis of primary cultured hepatocytes
AU - Kano, Arihiro
AU - Haruyama, Takahiro
AU - Akaike, Toshihiro
AU - Watanabe, Yoshifumi
N1 - Funding Information:
We thank Drs. T. Taniguchi and T. Tanaka in University of Tokyo for the generous gift of IRF-1-deficient mice. This work was supported in part by the grant of Suzuken Memorial Foundation.
PY - 1999/4/21
Y1 - 1999/4/21
N2 - IFN-γ induces cell cycle arrest and p53-independent apoptosis in primary cultured hepatocytes. However, it is not yet understood what molecules regulate the mechanism. We report here that interferon regulatory factor 1 (IRF-1) is an essential molecule in these phenomena. Hepatocytes from IRF-1-deficient mice were completely resistant to IFN-γ in apoptosis indicated by three different hallmarks such as LDH release, DNA fragmentation and the activation of caspase-3 family. Caspase-1 expression was little detected in hepatocytes, and constitutive and IFN-γ-induced mRNA expression of Fas or caspase-3 did not change in between wild type and IRF-1-deficient hepatocytes. Expression of IFN-γ-inducible caspase, caspase-11, did not change either. Thus, it is unlikely that these molecules directly regulate the mechanisms. Interestingly, IRF-1-deficient hepatocytes were also resistant to IFN-γ-induced cell cycle arrest despite IFN-γ-induced cell cycle arrest and apoptosis are regulated by independent pathways. Results by Northern blot analysis showed that IFN-γ-induced but not constitutive p53 mRNA expression was regulated by IRF-1. In fact, IFN-γ did not induce cell cycle arrest in p53-deficient hepatocytes. Taken together, IRF-1 mediates IFN-γ signaling into primary hepatocytes for cell cycle arrest via p53 expression and for apoptosis.
AB - IFN-γ induces cell cycle arrest and p53-independent apoptosis in primary cultured hepatocytes. However, it is not yet understood what molecules regulate the mechanism. We report here that interferon regulatory factor 1 (IRF-1) is an essential molecule in these phenomena. Hepatocytes from IRF-1-deficient mice were completely resistant to IFN-γ in apoptosis indicated by three different hallmarks such as LDH release, DNA fragmentation and the activation of caspase-3 family. Caspase-1 expression was little detected in hepatocytes, and constitutive and IFN-γ-induced mRNA expression of Fas or caspase-3 did not change in between wild type and IRF-1-deficient hepatocytes. Expression of IFN-γ-inducible caspase, caspase-11, did not change either. Thus, it is unlikely that these molecules directly regulate the mechanisms. Interestingly, IRF-1-deficient hepatocytes were also resistant to IFN-γ-induced cell cycle arrest despite IFN-γ-induced cell cycle arrest and apoptosis are regulated by independent pathways. Results by Northern blot analysis showed that IFN-γ-induced but not constitutive p53 mRNA expression was regulated by IRF-1. In fact, IFN-γ did not induce cell cycle arrest in p53-deficient hepatocytes. Taken together, IRF-1 mediates IFN-γ signaling into primary hepatocytes for cell cycle arrest via p53 expression and for apoptosis.
UR - http://www.scopus.com/inward/record.url?scp=0033590929&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033590929&partnerID=8YFLogxK
U2 - 10.1006/bbrc.1999.0276
DO - 10.1006/bbrc.1999.0276
M3 - Article
C2 - 10208842
AN - SCOPUS:0033590929
VL - 257
SP - 672
EP - 677
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 3
ER -