Interferon-gamma induced cell death: Regulation and contributions of nitric oxide, cJun N-terminal kinase, reactive oxygen species and peroxynitrite

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Highlights

  • Ifnγ-mediated cell death is dependent on the induction of RNI and ROS.

  • Ifnγ-induced NO is the major signaling initiator leading to apoptosis.

  • Induction of NADPH oxidase and mitochondrial ROS by Ifnγ contribute to cellular ROS.

  • JNK, ROS and peroxynitrite act as the effectors of cell death in response to Ifnγ.

  • Elevation of NO or ROS together with Ifnγ induces death of resistant cell lines.

Abstract

Interferon-gamma (Ifnγ), a known immunomodulatory cytokine, regulates cell proliferation and survival. In this study, the mechanisms leading to the selective susceptibility of some tumor cells to Ifnγ were deciphered. Seven different mouse tumor cell lines tested demonstrated upregulation of MHC class I to variable extents with Ifnγ; however, only the cell lines, H6 hepatoma and L929 fibrosarcoma, that produce higher amounts of nitric oxide (NO) and reactive oxygen species (ROS) are sensitive to Ifnγ-induced cell death. NO inhibitors greatly reduce Ifnγ-induced ROS; however, ROS inhibitors did not affect the levels of Ifnγ-induced NO, demonstrating that NO regulates ROS. Consequently, NO inhibitors are more effective, compared to ROS inhibitors, in reducing Ifnγ-induced cell death. Further analysis revealed that Ifnγ induces peroxynitrite and 3-nitrotyrosine amounts and a peroxynitrite scavenger, FeTPPS, reduces cell death. Ifnγ treatment induces the phosphorylation of c-jun N-terminal kinase (Jnk) in H6 and L929 but not CT26, a colon carcinoma cell line, which is resistant to Ifnγ-mediated death. Jnk activation downstream to NO leads to induction of ROS, peroxynitrite and cell death in response to Ifnγ. Importantly, three cell lines tested, i.e. CT26, EL4 and Neuro2a, that are resistant to cell death with Ifnγ alone become sensitive to the combination of Ifnγ and NO donor or ROS inducer in a peroxynitrite-dependent manner. Overall, this study delineates the key roles of NO as the initiator and Jnk, ROS, and peroxynitrite as the effectors during Ifnγ-mediated cell death. The implications of these findings in the Ifnγ-mediated treatment of malignancies are discussed.

Abbreviations

AG
aminoguanidine
BrdU
bromodeoxyuridine
DAF2DA
4, 5-diaminofluorescein diacetate
DCFDA
2′, 7′-dichlorofluorescin diacetate
DHR123
dihydrorhodamine 123
FeTPPS
5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrinato iron (III), chloride
FITC
fluorescein isothiocyanate
Ifnγ
interferon-gamma
IfnγR
interferon-gamma receptor
Irf1
interferon regulated factor 1
JC-1
5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide
Jnk
cJun-N-terminal kinase
Lmp10
proteasome (prosome, macropain) subunit beta type 10
LNMA
NG-methyl-l-arginine
LPS
lipopolysaccharide
MHC-I
Major Histocompatibility Complex encoded Class I
NO
nitric oxide
Nos2
nitric oxide synthase 2
3-NT
3-nitro tyrosine
PEG–CAT
polyethyleneglycol–catalase
PEG–SOD
polyethyleneglycol–superoxide dismutase
ROS
reactive oxygen species
RNI
reactive nitrogen intermediates
SNAP
S-Nitroso-N-acetyl-DL-penicillamine
Stat1
signal transducer and activator of transcription 1
t-BHP
tert-butyl hydroperoxide
ΔΨm
loss of mitochondrial membrane potential

Keywords

Interferon-gamma
Cell death
Oxidative stress
Nitrosative stress
Mitogen activated protein kinase
Free radical

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