Reduction of nitric oxide synthase 2 expression by distamycin A improves survival from endotoxemia
| Autor: | Irvith M. Carvajal, Xiaoli Liu, Rebecca M. Baron, Matthew D. Layne, Alvaro Macias, Yen-Hsu Chen, Laura E. Fredenburgh, Rachel Okabe, Mark A. Perrella, Kuniaki Ejima |
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| Rok vydání: | 2004 |
| Předmět: |
Lipopolysaccharides
Male Immunology Nitric Oxide Synthase Type II Cell Line chemistry.chemical_compound Interferon-gamma Mice In vivo parasitic diseases Immunology and Allergy Animals Enzyme Inhibitors Enhancer Overproduction Promoter Regions Genetic Transcription factor Cells Cultured Mice Knockout biology Distamycins Nitric oxide synthase 2 respiratory system Phosphoproteins Molecular biology In vitro Endotoxemia DNA binding site DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal chemistry Gene Expression Regulation Enzyme Induction biology.protein Macrophages Peritoneal Hypotension Nitric Oxide Synthase DNA Interferon Regulatory Factor-1 Protein Binding |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 173(6) |
| ISSN: | 0022-1767 |
| Popis: | NO synthase 2 (NOS2) plays an important role in endotoxemia through overproduction of NO. Distamycin A (Dist A) belongs to a class of drugs termed minor-groove DNA binders, which can inhibit transcription factor binding to AT-rich regions of DNA. We and others have previously shown that AT-rich regions of DNA surrounding transcription factor binding sites in the NOS2 promoter are critical for NOS2 induction by inflammatory stimuli in vitro. Therefore, we hypothesized that Dist A would attenuate NOS2 up-regulation in vivo during endotoxemia and improve animal survival. C57BL/6 wild-type (WT) mice treated with Dist A and LPS (endotoxin) showed significantly improved survival compared with animals treated with LPS alone. In contrast, LPS-treated C57BL/6 NOS2-deficient (NOS2−/−) mice did not benefit from the protective effect of Dist A on mortality from endotoxemia. Treatment with Dist A resulted in protection from hypotension in LPS-treated WT mice, but not in NOS2−/− mice. Furthermore, LPS-induced NOS2 expression was attenuated in vivo (WT murine tissues) and in vitro (primary peritoneal and RAW 264.7 murine macrophages) with addition of Dist A. Dist A selectively decreased IFN regulatory factor-1 DNA binding in the enhancer region of the NOS2 promoter, and this IFN regulatory factor-1 site is critical for the effect of Dist A in attenuating LPS induction of NOS2. Our data point to a novel approach in modulating NOS2 expression in vivo during endotoxemia and suggest the potential for alternative treatment approaches for critical illness. |
| Databáze: | OpenAIRE |
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