Increased mortality and inflammation in tumor necrosis factor-stimulated gene-14 transgenic mice after ischemia and reperfusion injury.
TSG-14/PTX3 is a gene inducible by tumor necrosis factor (TNF)-alpha, interleukin-1 beta, and lipopolysaccharide in fibroblasts, macrophages, and endothelial cells. It encodes a 42-kd secreted glycoprotein that belongs to the pentraxin family of acute-phase proteins. Recently, we demonstrated that TSG-14 transgenic mice (TSG-14tg) overexpressing the murine TSG-14 gene under control of its own promoter are more resistant to lipopolysaccharide-induced shock and to polymicrobial sepsis caused by cecal ligation and puncture. Here we show that after ischemia and reperfusion (I/R) injury, TSG-14tg mice have an impaired survival rate, which appeared secondary to a markedly increased inflammatory response, as assessed by the local (duodenum and ileum) and remote (lung) enhancement in vascular permeability, hemorrhage, and neutrophil accumulation. Moreover, tissue concentrations of TNF-alpha, interleukin-1 beta, KC, and MCP-1 were higher in TSG-14tg as compared to wild-type mice after I/R injury. Of note, elevated TNF-alpha concentrations in serum were only observed in TSG-14tg mice and blockage of TNF-alpha action prevented lethality of TSG-14tg mice. These results demonstrate that transgenic expression of TSG-14 induces an enhanced local and systemic injury and TNF-alpha-dependent lethality after I/R. Taken together, our data point to a critical role of TSG-14 in controlling acute inflammatory response in part via the modulation of TNF-alpha expression.
Souza
Danielle G
DG
Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Soares
Adriana C
AC
Pinho
Vanessa
V
Torloni
Humberto
H
Reis
Luiz F L
LF
Teixeira
Mauro M
MM
Dias
Adriana A M
AA
Martins
Mauro T
MT
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D002097:C-Reactive Protein / Q000235:genetics / Q000502:physiology*; D002199:Capillary Permeability / Q000502:physiology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004386:Duodenum / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005838:Genotype; D007249:Inflammation / Q000209:etiology / Q000473:pathology*; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D015427:Reperfusion Injury / Q000150:complications / Q000401:mortality / Q000503:physiopathology*; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000502:physiology*; D015996:Survival Rate; D013997:Time Factors; D000099153:Pentraxins
D015703:Antigens, CD; D002097:C-Reactive Protein; D018925:Chemokines; D016207:Cytokines; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D000683:Serum Amyloid P-Component; D000099153:Pentraxins