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Nitric Oxide Down-regulates Hepatocyte–Inducible Nitric Oxide Synthase Gene Expression

Bradley S. Taylor, MD; Young-Myeong Kim, PhD; Qi Wang; Richard A. Shapiro; Timothy R. Billiar, MD; David A. Geller, MD
Arch Surg. 1997;132(11):1177-1183. doi:10.1001/archsurg.1997.01430350027005.
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Background:  The expression of inducible nitric oxide synthase (iNOS) contributes to the systemic manifestations of sepsis.

Objective:  To determine whether nitric oxide (NO) can exert negative feedback regulation on iNOS gene expression.

Setting:  Molecular biology research laboratory of the department of surgery.

Study Design:  Isolated rat hepatocytes were cultured with a cytokine mix consisting of tumor necrosis factor α, interleukin 1β, and interferon γ in the presence or absence of the NO donor S-nitroso-N-acetyl-d,l-penicillamine.

Main Outcome Measures:  Nitrite and nitrate (NO2 and NO3) levels were assayed. Hepatocyte iNOS messenger RNA and protein levels were assessed. Electromobility shift assays were performed for NF-κB DNA binding activity. Finally, iNOS enzyme activity was determined using high-performance liquid chromatography.

Results:  Cytokine mix–induced hepatocyte iNOS mRNA and protein production and the addition of the NO donor S-nitroso-N-acetyl-d,l-penicillamine markedly attenuated iNOS mRNA and protein levels. Gel shift assays of the nuclear extracts disclosed that decreased cytokine mix–induced DNA binding activity for NF-κB in a concentration-dependent manner. Finally, NO failed to significantly inhibit iNOS enzyme activity.

Conclusions:  These data indicate that NO down-regulates iNOS gene transcription, and that the effect is mediated in part by inhibiting NF-κB activity. These results identify a novel negative feedback mechanism whereby NO down-regulates iNOS gene expression, possibly to limit overproduction during the septic response.Arch Surg. 1997;132:1177-1183


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