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
Identifiers and Pagination:Year: 2008
First Page: 1
Last Page: 9
Publisher Id: CCGTM-2-1
Article History:Received Date: 11/6/2008
Revision Received Date: 15/8/2008
Acceptance Date: 20/8/2008
Electronic publication date: 27/9/2008
Collection year: 2008
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.
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.