IRF-1 is an essential mediator in IFN-gamma-induced cell cycle arrest and apoptosis of primary cultured hepatocytes.

IFN-gamma 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-gamma 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-gamma-induced mRNA expression of Fas or caspase-3 did not change in between wild type and IRF-1-deficient hepatocytes. Expression of IFN-gamma-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-gamma-induced cell cycle arrest despite IFN-gamma-induced cell cycle arrest and apoptosis are regulated by independent pathways. Results by Northern blot analysis showed that IFN-gamma-induced but not constitutive p53 mRNA expression was regulated by IRF-1. In fact, IFN-gamma did not induce cell cycle arrest in p53-deficient hepatocytes. Taken together, IRF-1 mediates IFN-gamma signaling into primary hepatocytes for cell cycle arrest via p53 expression and for apoptosis.

[1]  V. L. Johnson,et al.  Fas‐mediated apoptosis in mouse hepatocytes involves the processing and activation of caspases , 1998, Hepatology.

[2]  Junying Yuan,et al.  Murine Caspase-11, an ICE-Interacting Protease, Is Essential for the Activation of ICE , 1998, Cell.

[3]  N. Thornberry,et al.  A Combinatorial Approach Defines Specificities of Members of the Caspase Family and Granzyme B , 1997, The Journal of Biological Chemistry.

[4]  P. Fitzpatrick,et al.  Interferon-γ Modulates a p53-independent Apoptotic Pathway and Apoptosis-related Gene Expression* , 1997, The Journal of Biological Chemistry.

[5]  D. Harrison,et al.  p53 deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  S. Nagata,et al.  Essential roles of the Fas ligand in the development of hepatitis , 1997, Nature Medicine.

[7]  T. Akaike,et al.  Analysis of IFN-gamma-induced cell cycle arrest and cell death in hepatocytes. , 1997, Journal of biochemistry.

[8]  D. Livingston.  In vitro and in vivo studies of ICE inhibitors , 1997, Journal of cellular biochemistry.

[9]  H. Mohri,et al.  Interferon-γ InducesIceGene Expression and Enhances Cellular Susceptibility to Apoptosis in the U937 Leukemia Cell Line ☆ , 1996 .

[10]  T. Akaike,et al.  Concanavalin A induces perforin‐mediated but not Fas‐mediated hepatic injury , 1996, Hepatology.

[11]  T. Taniguchi,et al.  Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage , 1996, Nature.

[12]  Junying Yuan,et al.  Identification and Characterization of Ich-3, a Member of the Interleukin-1β Converting Enzyme (ICE)/Ced-3 Family and an Upstream Regulator of ICE* , 1996, The Journal of Biological Chemistry.

[13]  H. Fujiwara,et al.  Critical involvement of interferon γ in the pathogenesis of T‐cell activation‐associated hepatitis and regulatory mechanisms of interleukin‐6 for the manifestations of hepatitis , 1996, Hepatology.

[14]  Xin-Yuan Fu,et al.  Cell Growth Arrest and Induction of Cyclin-Dependent Kinase Inhibitor p21WAF1/CIP1 Mediated by STAT1 , 1996, Science.

[15]  S. Nagata,et al.  Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis , 1996, Nature.

[16]  R. Schreiber,et al.  Targeted Disruption of the Stat1 Gene in Mice Reveals Unexpected Physiologic Specificity in the JAK–STAT Signaling Pathway , 1996, Cell.

[17]  D. Levy,et al.  Targeted Disruption of the Mouse Stat1 Gene Results in Compromised Innate Immunity to Viral Disease , 1996, Cell.

[18]  M. Oren,et al.  Specific loss of apoptotic but not cell‐cycle arrest function in a human tumor derived p53 mutant. , 1996, The EMBO journal.

[19]  S. Benchimol,et al.  Cytokines inhibit p53-mediated apoptosis but not p53-mediated G1 arrest , 1995, Molecular and cellular biology.

[20]  T. Taniguchi,et al.  An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphocytes , 1995, Nature.

[21]  T. Akaike,et al.  Protective effect of hepatocyte growth factor on interferon‐gamma—induced cytotoxicity in mouse hepatocytes , 1995, Hepatology.

[22]  I. Kerr,et al.  Jaks and Stats in signaling by the cytokine receptor superfamily. , 1995, Trends in genetics : TIG.

[23]  T. Taniguchi,et al.  Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1 , 1994, Cell.

[24]  O. Silvennoinen,et al.  Signaling by the cytokine receptor superfamily: JAKs and STATs. , 1994, Trends in biochemical sciences.

[25]  T. Taniguchi,et al.  Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. , 1994, Science.

[26]  Yoshifumi Watanabe,et al.  Inflammatory cytokines up‐regulate intercellular adhesion molecule‐1 expression on primary cultured mouse hepatocytes and T‐lymphocyte adhesion , 1994, Hepatology.

[27]  T. Taniguchi,et al.  Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development , 1993, Cell.

[28]  S. Nagata,et al.  Lethal effect of the anti-Fas antibody in mice , 1993, Nature.

[29]  F. Schaper,et al.  Interferon regulatory factor 1 (IRF-1) mediates cell growth inhibition by transactivation of downstream target genes. , 1993, Nucleic acids research.

[30]  T. Blankenstein,et al.  Kinetic analysis of cytokine gene expression in the livers of naive and immune mice infected with Listeria monocytogenes. The immediate early phase in innate resistance and acquired immunity. , 1992, Journal of immunology.

[31]  F. Chisari,et al.  HBsAg retention sensitizes the hepatocyte to injury by physiological concentrations of interferon‐γ , 1992 .

[32]  F. Chisari,et al.  Immunology and the liver , 1991, Hepatology.

[33]  R. Vos,et al.  Expression of interferon-γ receptor in normal and pathological human liver tissue , 1991 .

[34]  D. Muir,et al.  An enzyme-linked immunosorbent assay for bromodeoxyuridine incorporation using fixed microcultures. , 1990, Analytical biochemistry.

[35]  K. Yoshioka,et al.  Tumor necrosis factor α production by peripheral blood mononuclear cells of patients with chronic liver disease , 1989 .

[36]  C. McClain,et al.  Increased tumor necrosis factor production by monocytes in alcoholic hepatitis , 1989, Hepatology.

[37]  V. Barnaba,et al.  Expression of class I and class II major histocompatibility complex antigens on human hepatocytes , 1988, Hepatology.

[38]  C. Korzeniewski,et al.  An enzyme-release assay for natural cytotoxicity. , 1983, Journal of immunological methods.

[39]  C. Unger,et al.  Wild-type function of the p53 tumor suppressor protein is not required for apoptosis of mouse hepatoma cells , 1998, Cell Death and Differentiation.