| First Author | Rakshit S | Year | 2014 |
| Journal | Biochim Biophys Acta | Volume | 1843 |
| Issue | 11 | Pages | 2645-61 |
| PubMed ID | 24983769 | Mgi Jnum | J:218501 |
| Mgi Id | MGI:5617685 | Doi | 10.1016/j.bbamcr.2014.06.014 |
| Citation | Rakshit S, et al. (2014) Interferon-gamma induced cell death: Regulation and contributions of nitric oxide, cJun N-terminal kinase, reactive oxygen species and peroxynitrite. Biochim Biophys Acta 1843(11):2645-61 |
| abstractText | Interferon-gamma (Ifngamma), a known immunomodulatory cytokine, regulates cell proliferation and survival. In this study, the mechanisms leading to the selective susceptibility of some tumor cells to Ifngamma were deciphered. Seven different mouse tumor cell lines tested demonstrated upregulation of MHC class I to variable extents with Ifngamma; 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 Ifngamma-induced cell death. NO inhibitors greatly reduce Ifngamma-induced ROS; however, ROS inhibitors did not affect the levels of Ifngamma-induced NO, demonstrating that NO regulates ROS. Consequently, NO inhibitors are more effective, compared to ROS inhibitors, in reducing Ifngamma-induced cell death. Further analysis revealed that Ifngamma induces peroxynitrite and 3-nitrotyrosine amounts and a peroxynitrite scavenger, FeTPPS, reduces cell death. Ifngamma 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 Ifngamma-mediated death. Jnk activation downstream to NO leads to induction of ROS, peroxynitrite and cell death in response to Ifngamma. Importantly, three cell lines tested, i.e. CT26, EL4 and Neuro2a, that are resistant to cell death with Ifngamma alone become sensitive to the combination of Ifngamma 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 Ifngamma-mediated cell death. The implications of these findings in the Ifngamma-mediated treatment of malignancies are discussed. |
