Signaling mechanisms of interferon gamma induced apoptosis in chromaffin cells: involvement of nNOS, iNOS, and NFκB
Article first published online: 22 DEC 2008
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 108, Issue 4, pages 1083–1096, February 2009
How to Cite
Pérez-Rodríguez, R., Roncero, C., Oliván, A. M., González, M. P. and Oset-Gasque, M. J. (2009), Signaling mechanisms of interferon gamma induced apoptosis in chromaffin cells: involvement of nNOS, iNOS, and NFκB. Journal of Neurochemistry, 108: 1083–1096. doi: 10.1111/j.1471-4159.2008.05862.x
- Issue published online: 19 JAN 2009
- Article first published online: 22 DEC 2008
- Received December 2, 2008; revised manuscript received December 6, 2008; accepted December 8, 2008.
- cell death;
- chromaffin cells;
- nuclear factor κB;
- nitric oxide synthase;
- signal transduction
Previous work of our group stated that exogenously added and endogenous nitric oxide (NO) generated by cytokines induce apoptosis in chromaffin cells. In this work, we investigate the specific regulation of the NO synthase (NOS) isoforms, inducible NOS (iNOS) and neuronal NOS (nNOS), and their particular participation in cell death induced by interferon gamma (IFNγ). Lipopolysaccharide (LPS) and IFNγ increase iNOS expression, with no effect on nNOS expression. On the other hand, dexamethasone increases basal nNOS expression but decreases LPS + IFNγ-induced iNOS expression. IFNγ-induced cell death was abolished by W-1400, a specific iNOS inhibitor, but only partially by nNOS inhibitors [N-ω-propyl-l-arginine (N-PLA), 3-Bromo-7-nitroindazol (7-NI), l-methyl thiocitrulline and N-methyl l-arginine], indicating the main iNOS participation in chromaffin cell death. IFNγ and LPS induce nuclear factor κB (NFκB) translocation to the nucleus, a process implicated in activation of iNOS expression, as inhibition of NFκB translocation, by SN50, decreased iNOS expression. In addition, IFNγ and LPS induce 847Ser-nNOS phosphorylation, inhibiting nNOS activity. Both processes, nNOS phosphorylation and iNOS expression induced by LPS + IFNγ, are regulated by Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway, as IFNγ increases 727STAT-3 phosphorylation and specific inhibitors of JAK/STAT pathway, such as AG490, inhibited both processes. Taken together, these results support the hypothesis of an inactivating phosphorylation of nNOS by IFNγ, via JAK/STAT, in bovine chromaffin cells. Low NO concentrations achieved by this event, would activate NFκB translocation, increasing iNOS expression and generating, this last, high apoptotic NO concentrations.