Increased mortality, blunted production of nitric oxide, and increased production of TNF-α in endotoxemic TGF-β1 transgenic mice

Yoram Vodovotz*, Jeffrey B. Kopp, Heather Takeguchi, Shashi Shrivastav, Deborah Coffin, M. Scott Lucia, James B. Mitchell, Robert Webber, John Letterio, David Wink, Anita B. Roberts

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

The expression of the inducible isoform of nitric oxide synthase (NOS2, iNOS) is increased in patients undergoing sepsis as well as in animal models in which septic shock is induced by injection of bacterial lipopolysaccharide (LPS). Transforming growth factor-β1 (TGF-β1) potently suppresses NO production both in vitro and in vivo. After intraperitoneal injection of LPS, mice over-expressing a cDNA coding for active TGF-β1 in the liver (Alb/TGF- β1) exhibited reduced serum levels of the NO reaction products NO2- + NO3- compared with controls. Paradoxically, while endotoxemic Alb/TGF-β1 mice expressed much less NOS2 protein in peritoneal exudate cells than did endotoxemic wild-type mice, Alb/TGF-β1 mice expressed more NOS2 mRNA and protein in both liver and kidney. Alb/TGF-β1 mice treated with LPS had eightfold higher serum tumor necrosis factor α (TNF-α) levels and experienced increased mortality compared with wild-type mice, which was associated with renal insufficiency. These results suggest that renal dysfunction, decreased production of NO, and/or increased production of TNF- α are associated with increased mortality of endotoxemic Alb/TGF-β1 mice.

Original languageEnglish
Pages (from-to)31-39
Number of pages9
JournalJournal of Leukocyte Biology
Volume63
Issue number1
DOIs
StatePublished - 1998
Externally publishedYes

Keywords

  • NOS2
  • Septic shock

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