title: Inhibition of inducible nitric oxide synthase expression by a novel small molecule activator of the unfolded protein response.
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 eIF2alpha 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.
authors.affiliation: Department of Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Kent T
authors.initials: KT
authors.lastname: Symons
authors.forename: Mark E
authors.initials: ME
authors.lastname: Massari
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Dozier
authors.forename: Phan M
authors.initials: PM
authors.lastname: Nguyen
authors.forename: David
authors.initials: D
authors.lastname: Jenkins
authors.forename: Mark
authors.initials: M
authors.lastname: Herbert
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Gahman
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Noble
authors.forename: Natasha
authors.initials: N
authors.lastname: Rozenkrants
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tadimeti S
authors.initials: TS
authors.lastname: Rao
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Shiau
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hassig