IRF-1 Is an Essential Mediator in IFN-γ-Induced Cell Cycle Arrest and Apoptosis of Primary Cultured Hepatocytes

Kano, Arihiro; Haruyama, Takahiro; Akaike, Toshihiro; Watanabe, Yoshifumi

doi:10.1006/bbrc.1999.0276

Cited by 135 publications

(122 citation statements)

References 42 publications

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“…IFN-␥ induces susceptibility to TNF-␣-mediated apoptosis by sequentially activating or inducing STAT1 and IRF-1. Previous studies have indicated the role of IRF-1 in apoptosis induced by DNA damage or IFN-␥ (30,31,42), which supported the proapoptotic action of IRF-1. However, the role of IRF-1 in conferring susceptibility to TNF-␣-induced apoptosis has not been reported.…”

Section: Discussionmentioning

confidence: 71%

“…In our model, IFN-␥ plays a priming role for the cytotoxic action of TNF-␣ in pancreatic islet cells, and this priming role of IFN-␥ is mediated by IRF-1 induction. Although previous reports showed that IFN-␥ alone could induce apoptosis on various types of cells, such as primary hepatocytes (31) or HeLa, (55) through IRF-1 induction, the cytokine seems to require another cytotoxic signaling event to kill islet ␤ cells.…”

Section: Discussionmentioning

confidence: 90%

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IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

Suk

Kim

et al. 2001

The Journal of Immunology

209

187

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Fas ligand (FasL), perforin, TNF-α, IL-1, and NO have been considered as effector molecule(s) leading to β cell death in autoimmune diabetes. However, the real culprit(s) in β cell destruction have long been elusive, despite intense investigation. We and others have demonstrated that FasL is not a major effector molecule in autoimmune diabetes, and previous inability to transfer diabetes to Fas-deficient nonobese diabetic (NOD)-lpr mice was due to constitutive FasL expression on lymphocytes from these mice. Here, we identified IFN-γ/TNF-α synergism as the final effector molecules in autoimmune diabetes of NOD mice. A combination of IFN-γ and TNF-α, but neither cytokine alone, induced classical caspase-dependent apoptosis in insulinoma and pancreatic islet cells. IFN-γ treatment conferred susceptibility to TNF-α-induced apoptosis on otherwise resistant insulinoma cells by STAT1 activation followed by IFN regulatory factor (IRF)-1 induction. IRF-1 played a central role in IFN-γ/TNF-α-induced cytotoxicity because inhibition of IRF-1 induction by antisense oligonucleotides blocked IFN-γ/TNF-α-induced cytotoxicity, and transfection of IRF-1 rendered insulinoma cells susceptible to TNF-α-induced cytotoxicity. STAT1 and IRF-1 were expressed in pancreatic islets of diabetic NOD mice and colocalized with apoptotic cells. Moreover, anti-TNF-α Ab inhibited the development of diabetes after adoptive transfer. Taken together, our results indicate that IFN-γ/TNF-α synergism is responsible for autoimmune diabetes in vivo as well as β cell apoptosis in vitro and suggest a novel signal transduction in IFN-γ/TNF-α synergism that may have relevance in other autoimmune diseases and synergistic anti-tumor effects of the two cytokines.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 90%

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

Suk

Kim

et al. 2001

The Journal of Immunology

209

187

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“…For example, expression of oncogenic c-ras caused normal fibroblasts but not IRF7/7 fibroblasts to undergo death when combined with inhibitors of cellular proliferation or when treated by anticancer drugs or UV irradiation. 72,73 Similarly, IRF-1 has been reported to mediate DNA-damage-induced apoptosis in T lymphocytes and to regulate cell cycle arrest and apoptosis in primary hepatocytes in response to IFN-g signaling. Myeloid cells but not thymocytes derived from ICSBP (IRF-8) deficient mice also show resistance to apoptosis induced by DNA damage.…”

Section: The Ifn Regulatory Factors (Irfs)mentioning

confidence: 99%

Host defense, viruses and apoptosis

2001

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“…A large number of studies have revealed the versatile and critical functions performed by IRF family in innate immunity [56–58], adaptive immunity [57] and many other biological processes, such as immune cell development [56,58], regulation of gene expression in response to pathogen infection [56,59,60],regulation of the cell cycle [61,62] and apoptosis [63,64]. The MAF is a family of transcription factor protein that belongs to the activated protein-1 super-family of transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

Hu¹,

Hu²,

Wang³

et al. 2018

Virulence

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Long non-coding RNAs (lncRNAs) play multiple key regulatory roles in various biological processes. However, their function in influenza A virus (IAV) pathogenicity remains largely unexplored. Here, using next generation sequencing, we systemically compared the whole-transcriptome response of the mouse lung infected with either the highly pathogenic (A/Chicken/Jiangsu/k0402/2010, CK10) or the nonpathogenic (A/Goose/Jiangsu/k0403/2010, GS10) H5N1 virus. A total of 126 significantly differentially expressed (SDE) lncRNAs from three replicates were identified to be associated with the high virulence of CK10, whereas 94 SDE lncRNAs were related with GS10. Functional category analysis suggested that the SDE lncRNAs-coexpressed mRNAs regulated by CK10 were highly related with aberrant and uncontrolled inflammatory responses. Further canonical pathway analysis also confirmed that these targets were highly enriched for inflammatory-related pathways. Moreover, 9 lncRNAs and 17 lncRNAs-coexpressed mRNAs associated with a large number of targeted genes were successfully verified by qRT-PCR. One targeted lncRNA (NONMMUT011061) that was markedly activated and correlated with a great number of mRNAs was selected for further in-depth analysis, including predication of transcription factors, potential interacting proteins, genomic location, coding ability and construction of the secondary structure. More importantly, NONMMUT011061 was also distinctively stimulated during the highly pathogenic H5N8 virus infection in mice, suggesting a potential universal role of NONMMUT011061 in the pathogenesis of different H5 IAV. Altogether, these results provide a subset of lncRNAs that might play important roles in the pathogenesis of influenza virus and add the lncRNAs to the vast repertoire of host factors utilized by IAV for infection and persistence.

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IRF-1 Is an Essential Mediator in IFN-γ-Induced Cell Cycle Arrest and Apoptosis of Primary Cultured Hepatocytes

Cited by 135 publications

References 42 publications

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

Host defense, viruses and apoptosis

Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

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