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Inhibition of inducible nitric oxide synthase expression by a novel small molecule activator of the unfolded protein response.

Symons KT, Massari ME, Dozier SJ, Nguyen PM, Jenkins D, Herbert M, Gahman TC, Noble SA, Rozenkrants N, Zhang Y, Rao TS, Shiau AK, Hassig CA - Curr Chem Genomics (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.

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.

No MeSH data available.


Plasma nitrate/nitrite levels, an indirect measure of iNOS activity, in normal animals and animals challenged with bacterial lipopolysaccharide (LPS), with or without coadministration of erstressin (Es) dosed at 30 mg/kg via intraperitoneal injection. Drug and LPS were administered simultaneously and plasma nitrates were measured at 6 hours post-challenge. Each data point represents mean ± SE from 4-5 animals/ group, * p < 0.001.
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Figure 5: Plasma nitrate/nitrite levels, an indirect measure of iNOS activity, in normal animals and animals challenged with bacterial lipopolysaccharide (LPS), with or without coadministration of erstressin (Es) dosed at 30 mg/kg via intraperitoneal injection. Drug and LPS were administered simultaneously and plasma nitrates were measured at 6 hours post-challenge. Each data point represents mean ± SE from 4-5 animals/ group, * p < 0.001.

Mentions: To evaluate the potential of erstressin to suppress iNOS expression in vivo, we determined the effects of erstressin on NO production in a model of inflammatory disease. Administration of LPS to rodents induces a systemic inflammatory response coincident with expression of iNOS [16]. Consistent with its ability to reduce iNOS activity in cell culture, intraperitoneal administration of erstressin reduced NO metabolites in rat plasma following LPS stimulation by 50% relative to vehicle, p<0.001 (Fig. 5). In a separate experiment, the potent iNOS inhibitor, 1400W, was tested as a comparator in the LPS model (Supplemental Fig. 3). Although 1400W is a more efficacious compound (76% reduction in NO metabolites; p<0.0001), the results are consistent with an ability of erstressin to downregulate iNOS in vivo during proinflammatory stimulation, providing for the possibility that a similar mechanism of action to that seen in cell culture experiments might downregulate iNOS in certain inflammatory disease settings.


Inhibition of inducible nitric oxide synthase expression by a novel small molecule activator of the unfolded protein response.

Symons KT, Massari ME, Dozier SJ, Nguyen PM, Jenkins D, Herbert M, Gahman TC, Noble SA, Rozenkrants N, Zhang Y, Rao TS, Shiau AK, Hassig CA - Curr Chem Genomics (2008)

Plasma nitrate/nitrite levels, an indirect measure of iNOS activity, in normal animals and animals challenged with bacterial lipopolysaccharide (LPS), with or without coadministration of erstressin (Es) dosed at 30 mg/kg via intraperitoneal injection. Drug and LPS were administered simultaneously and plasma nitrates were measured at 6 hours post-challenge. Each data point represents mean ± SE from 4-5 animals/ group, * p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2803434&req=5

Figure 5: Plasma nitrate/nitrite levels, an indirect measure of iNOS activity, in normal animals and animals challenged with bacterial lipopolysaccharide (LPS), with or without coadministration of erstressin (Es) dosed at 30 mg/kg via intraperitoneal injection. Drug and LPS were administered simultaneously and plasma nitrates were measured at 6 hours post-challenge. Each data point represents mean ± SE from 4-5 animals/ group, * p < 0.001.
Mentions: To evaluate the potential of erstressin to suppress iNOS expression in vivo, we determined the effects of erstressin on NO production in a model of inflammatory disease. Administration of LPS to rodents induces a systemic inflammatory response coincident with expression of iNOS [16]. Consistent with its ability to reduce iNOS activity in cell culture, intraperitoneal administration of erstressin reduced NO metabolites in rat plasma following LPS stimulation by 50% relative to vehicle, p<0.001 (Fig. 5). In a separate experiment, the potent iNOS inhibitor, 1400W, was tested as a comparator in the LPS model (Supplemental Fig. 3). Although 1400W is a more efficacious compound (76% reduction in NO metabolites; p<0.0001), the results are consistent with an ability of erstressin to downregulate iNOS in vivo during proinflammatory stimulation, providing for the possibility that a similar mechanism of action to that seen in cell culture experiments might downregulate iNOS in certain inflammatory disease settings.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.

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.

No MeSH data available.