LPS-induced liver injury in D-galactosamine-sensitized mice requires secreted TNF-alpha and the TNF-p55 receptor.
Lipopolysaccharide and D-galactosamine induced lethality and apoptotic liver injury is dependent on endogenously produced tumor necrosis factor (TNF)-alpha. The present study was undertaken to determine whether membrane-associated or secreted TNF-alpha signaling through the p55 or p75 receptor was responsible for survival and hepatic injury after lipopolysaccharide administration in D-galactosamine-sensitized mice. Transgenic mice expressing null forms of TNF-alpha, the p55 and p75 receptor, and mice expressing only a cell-associated form of TNF-alpha were challenged with 8 mg D-galactosamine and 100 ng lipopolysaccharide. Mortality and apoptotic liver injury were only seen in wild-type and p75 knockout mice. p75 Knockout mice had significantly higher concentrations of plasma TNF-alpha than any other experimental group (P </= 0.05) and tended to have the highest mortality and liver injury. In contrast, p55 and TNF-alpha knockout mice and animals expressing only a cell-associated form of TNF-alpha exhibited no mortality or liver injury. We conclude that survival and apoptotic liver injury in response to lipopolysaccharide and D-galactosamine are dependent exclusively on secreted TNF-alpha signaling through the p55 receptor.
Nowak
M
M
Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Gaines
G C
GC
Rosenberg
J
J
Minter
R
R
Bahjat
F R
FR
Rectenwald
J
J
MacKay
S L
SL
Edwards
C K
CK
Moldawer
L L
LL
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D005688:Galactosamine; D008070:Lipopolysaccharides; D008107:Liver Diseases / Q000401:mortality / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase