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Increased mortality, blunted production of nitric oxide, and increased production of TNF‐α in endotoxemic TGF‐β1 transgenic mice
Author(s) -
Vodovotz Yoram,
Kopp Jeffrey B.,
Takeguchi Heather,
Shrivastav Shashi,
Coffin Deborah,
Lucia M. Scott,
Mitchell James B.,
Webber Robert,
Letterio John,
Wink David,
Roberts Anita B.
Publication year - 1998
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.63.1.31
Subject(s) - lipopolysaccharide , nitric oxide , tumor necrosis factor alpha , in vivo , biology , transforming growth factor , medicine , endocrinology , sepsis , intraperitoneal injection , kidney , nitric oxide synthase , genetically modified mouse , cytokine , septic shock , transgene , immunology , biochemistry , microbiology and biotechnology , gene
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 NO 2 – + NO 3 – 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. J. Leukoc. Biol . 63: 31–39; 1998.