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Characterization of NO and cytokine production in immune-activated microglia and peritoneal macrophages derived from a mouse model expressing the human NOS2 gene on a mouse NOS2 knockout background.

Publication ,  Journal Article
Vitek, MP; Brown, C; Xu, Q; Dawson, H; Mitsuda, N; Colton, CA
Published in: Antioxid Redox Signal
2006

Significant differences exist in the production and release of nitric oxide (NO) from human macrophages versus macrophages of mouse origin. Human macrophages have been shown to respond poorly to stimuli that provoke strong inflammatory reactions from mouse macrophages. To address the differences in macrophage function in an animal model, a transgenic mouse was created that contained the entire human NOS2 gene, including the human promoter and all of its exons and introns. The huNOS2 transgenic mouse was then mated to mice lacking a functional NOS2 gene (muNOS2(/) or NOS2 knockout mice) to generate a double transgenic mouse (huNOS2(+/0)/muNOS2(/)) that expresses a functional human NOS2 gene in place of the mouse NOS2 gene. These double transgenic mice were found to express only human NOS2 mRNA and human iNOS proteins in response to immune stimulation. The production and release of nitric oxide from isolated macrophages from the doubly transgenic mouse also more closely paralleled human responses rather than mouse. Peritoneal macrophages from double transgenic mice generated nanomolar levels of nitrite in response to inflammatory stimuli, while peritoneal macrophages from wild-type mice generated micromolar levels of nitrite in response to the same inflammatory stimuli. Similarly, microglia from the huNOS2(+/0)/muNOS2(/) mice accumulated nanomolar levels of nitrite following inflammatory stimulation. Reduced nitrite release persisted in spite of normal responsiveness to inflammatory stimulation as measured by tumor necrosis factor alpha and interleukin-6 production and release. These data suggest that the human-specific release of nanomolar levels of nitrite may largely result from differences between the human and mouse NOS2 genes, which may program different degrees of nitric oxide responses to inflammatory signals in humans than in mice.

Duke Scholars

Published In

Antioxid Redox Signal

DOI

ISSN

1523-0864

Publication Date

2006

Volume

8

Issue

5-6

Start / End Page

893 / 901

Location

United States

Related Subject Headings

  • Nitrites
  • Nitric Oxide Synthase Type II
  • Nitric Oxide
  • Microglia
  • Mice, Transgenic
  • Mice, Knockout
  • Mice
  • Macrophages, Peritoneal
  • Macrophage Activation
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Vitek, M. P., Brown, C., Xu, Q., Dawson, H., Mitsuda, N., & Colton, C. A. (2006). Characterization of NO and cytokine production in immune-activated microglia and peritoneal macrophages derived from a mouse model expressing the human NOS2 gene on a mouse NOS2 knockout background. Antioxid Redox Signal, 8(5–6), 893–901. https://doi.org/10.1089/ars.2006.8.893
Vitek, Michael P., Candice Brown, Qing Xu, Hana Dawson, Noriaki Mitsuda, and Carol A. Colton. “Characterization of NO and cytokine production in immune-activated microglia and peritoneal macrophages derived from a mouse model expressing the human NOS2 gene on a mouse NOS2 knockout background.Antioxid Redox Signal 8, no. 5–6 (2006): 893–901. https://doi.org/10.1089/ars.2006.8.893.
Journal cover image

Published In

Antioxid Redox Signal

DOI

ISSN

1523-0864

Publication Date

2006

Volume

8

Issue

5-6

Start / End Page

893 / 901

Location

United States

Related Subject Headings

  • Nitrites
  • Nitric Oxide Synthase Type II
  • Nitric Oxide
  • Microglia
  • Mice, Transgenic
  • Mice, Knockout
  • Mice
  • Macrophages, Peritoneal
  • Macrophage Activation
  • Humans