RESEARCH ARTICLE


Inhibition of Inducible Nitric Oxide Synthase Expression by a Novel Small Molecule Activator of the Unfolded Protein Response



Kent T Symons1, Mark E Massari1, Sara J Dozier1, Phan M Nguyen1, David Jenkins1, Mark Herbert2, Timothy C Gahman2, Stewart A Noble2, Natasha Rozenkrants3, Yan Zhang3, Tadimeti S Rao3, Andrew K Shiau1, Christian A Hassig*, 1, 4
1 Department of Biology;The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA
2 Department of Chemistry;The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA
3 Department of Pharmacology, Kalypsys, Inc., 10420 Wateridge Circle, San Diego, CA 92121, USA; The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA
4 Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA


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© Symons et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA; E-mail: chassig@kalypsys.com


Abstract

The transcription of inducible nitric oxide synthase (iNOS) is activated by a network of proinflammatory signaling pathways. Here we describe the identification of a small molecule that downregulates the expression of iNOS mRNA and protein in cytokine-activated cells and suppresses nitric oxide production in vivo. Mechanistic analysis suggests that this small molecule, erstressin, also activates the unfolded protein response (UPR), a signaling pathway triggered by endoplasmic reticulum stress. Erstressin induces rapid phosphorylation of eIF2α and the alternative splicing of XBP-1, hallmark initiating events of the UPR. Further, erstressin activates the transcription of multiple genes involved in the UPR. These data suggest an inverse relationship between UPR activation and iNOS mRNA and protein expression under proinflammatory conditions.