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Dexamethasone inhibits the induction of iNOS gene expression through destabilization of its mRNA in proinflammatory cytokine-stimulated hepatocytes.
Shock 2010; 33(1):64-9S

Abstract

In the inflamed liver, proinflammatory cytokines including TNF-alpha, IL-1beta, and IFN-gamma stimulate the induction of iNOS gene expression, leading to excess production of NO and resulting in liver injury. The induction of iNOS is regulated by transactivation of the iNOS promoter with transcription factors such as nuclear factor kappaB and by posttranscriptional modifications such as mRNA stabilization. The synthetic glucocorticoid dexamethasone has been reported to inhibit iNOS induction, which may contribute to its inflammation-reducing effects. The objective was to investigate the mechanisms involved in the down-regulation of iNOS gene expression by dexamethasone. Primary cultured rat hepatocytes were treated with IL-1beta (1 nM) in the presence or absence of dexamethasone. The induction of iNOS and its signal were analyzed. Dexamethasone (10-250 nM) inhibited the expression of iNOS mRNA and protein dose and time dependently, resulting in decreases in NO production. However, dexamethasone did not inhibit the up-regulation of type I IL-1 receptor stimulated by IL-1beta. Dexamethasone also had no effect on the degradation of IkappaB proteins and on the activation of nuclear factor kappaB. Transfection experiments with iNOS promoter-luciferase constructs revealed that dexamethasone had no effect on the transactivation of the iNOS promoter but decreased the stabilization of iNOS mRNA. In support of the latter observation, dexamethasone inhibited the expression of an iNOS gene antisense transcript, which stabilizes iNOS mRNA by interacting with its 3'-untranslated region and 3'-untranslated region-binding proteins. Dexamethasone may inhibit the induction of iNOS gene expression at the step of mRNA stabilization rather than promoter activation and may provide useful therapeutic effects in iNOS induction involved in liver injuries.

Authors+Show Affiliations

Department of Surgery, Kansai Medical University, Moriguchi, Osaka, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19373131

Citation

Ozaki, Takashi, et al. "Dexamethasone Inhibits the Induction of iNOS Gene Expression Through Destabilization of Its mRNA in Proinflammatory Cytokine-stimulated Hepatocytes." Shock (Augusta, Ga.), vol. 33, no. 1, 2010, pp. 64-9.
Ozaki T, Habara K, Matsui K, et al. Dexamethasone inhibits the induction of iNOS gene expression through destabilization of its mRNA in proinflammatory cytokine-stimulated hepatocytes. Shock. 2010;33(1):64-9.
Ozaki, T., Habara, K., Matsui, K., Kaibori, M., Kwon, A. H., Ito, S., ... Okumura, T. (2010). Dexamethasone inhibits the induction of iNOS gene expression through destabilization of its mRNA in proinflammatory cytokine-stimulated hepatocytes. Shock (Augusta, Ga.), 33(1), pp. 64-9. doi:10.1097/SHK.0b013e3181a7fd74.
Ozaki T, et al. Dexamethasone Inhibits the Induction of iNOS Gene Expression Through Destabilization of Its mRNA in Proinflammatory Cytokine-stimulated Hepatocytes. Shock. 2010;33(1):64-9. PubMed PMID: 19373131.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dexamethasone inhibits the induction of iNOS gene expression through destabilization of its mRNA in proinflammatory cytokine-stimulated hepatocytes. AU - Ozaki,Takashi, AU - Habara,Kozo, AU - Matsui,Kosuke, AU - Kaibori,Masaki, AU - Kwon,A-Hon, AU - Ito,Seiji, AU - Nishizawa,Mikio, AU - Okumura,Tadayoshi, PY - 2009/4/18/entrez PY - 2009/4/18/pubmed PY - 2010/3/5/medline SP - 64 EP - 9 JF - Shock (Augusta, Ga.) JO - Shock VL - 33 IS - 1 N2 - In the inflamed liver, proinflammatory cytokines including TNF-alpha, IL-1beta, and IFN-gamma stimulate the induction of iNOS gene expression, leading to excess production of NO and resulting in liver injury. The induction of iNOS is regulated by transactivation of the iNOS promoter with transcription factors such as nuclear factor kappaB and by posttranscriptional modifications such as mRNA stabilization. The synthetic glucocorticoid dexamethasone has been reported to inhibit iNOS induction, which may contribute to its inflammation-reducing effects. The objective was to investigate the mechanisms involved in the down-regulation of iNOS gene expression by dexamethasone. Primary cultured rat hepatocytes were treated with IL-1beta (1 nM) in the presence or absence of dexamethasone. The induction of iNOS and its signal were analyzed. Dexamethasone (10-250 nM) inhibited the expression of iNOS mRNA and protein dose and time dependently, resulting in decreases in NO production. However, dexamethasone did not inhibit the up-regulation of type I IL-1 receptor stimulated by IL-1beta. Dexamethasone also had no effect on the degradation of IkappaB proteins and on the activation of nuclear factor kappaB. Transfection experiments with iNOS promoter-luciferase constructs revealed that dexamethasone had no effect on the transactivation of the iNOS promoter but decreased the stabilization of iNOS mRNA. In support of the latter observation, dexamethasone inhibited the expression of an iNOS gene antisense transcript, which stabilizes iNOS mRNA by interacting with its 3'-untranslated region and 3'-untranslated region-binding proteins. Dexamethasone may inhibit the induction of iNOS gene expression at the step of mRNA stabilization rather than promoter activation and may provide useful therapeutic effects in iNOS induction involved in liver injuries. SN - 1540-0514 UR - https://www.unboundmedicine.com/medline/citation/19373131/Dexamethasone_inhibits_the_induction_of_iNOS_gene_expression_through_destabilization_of_its_mRNA_in_proinflammatory_cytokine_stimulated_hepatocytes_ L2 - http://dx.doi.org/10.1097/SHK.0b013e3181a7fd74 DB - PRIME DP - Unbound Medicine ER -