ArticleProceedings of the National Academy of Sciences of the United States of America2000
Dominant negative down-regulation of endotoxin-induced tumor necrosis factor alpha production by Lps(d)/Ran.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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4 citing papers in PubMed, 17 citations in OpenAlex.
- Persistent Antigen Harbored by Alveolar Macrophages Enhances the Maintenance of Lung-Resident Memory CD8Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- An adenoviral vector for probing promoter activity in primary immune cells.Journal of immunological methods · 2006Article
- Genetic control of the innate immune response.BMC immunology · 2003Article
- Specific association of Type I c-Abl with Ran GTPase in lipopolysaccharide-mediated differentiation.Oncogene · 2001Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
We recently showed that adenoviral transfer and expression of the Lps(d)/Ran gene isolated from endotoxin-resistant C3H/HeJ mice could protect endotoxin-sensitive mice from endotoxic shock. Elevation of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), is thought to be essential for the development of septic shock. To investigate the extent to which Lps(d)/Ran affects TNF-alpha production, we transduced primary macrophages from endotoxin-sensitive and -resistant mice with adenoviral vectors expressing the wild-type and the mutant Lps/Ran cDNAs and other control genes, and compared the amount of TNF-alpha produced by these various transduced macrophages. Successful transfer and expression of Lps(d)/Ran cDNA in endotoxin-sensitive C3H/HeOuJ macrophages reduced TNF-alpha production upon lipopolysaccharide (LPS) stimulation, as compared with macrophages transduced with vectors expressing the wild-type Lps(n)/Ran cDNA, the green fluorescent protein gene, or the lacZ gene. On the other hand, successful transfer and expression of the wild-type Lps(n)/Ran cDNA in primary macrophages from endotoxin-resistant C3H/HeJ mice failed to induce TNF-alpha production to any significant extent unless a very high LPS concentration was used. Given our previous demonstration that Lps(n)/Ran functions effectively in restoring LPS responsiveness in B cells from C3H/HeJ mice, we conclude that Lps/Ran is involved in a CD14-independent signal transduction pathway. This dominant negative down-regulation by Lps(d)/Ran on TNF-alpha production by macrophages and probably other innate immune responses may be key to the development of an effective gene therapy for endotoxic or septic shock.
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