Differential response of a(2)-macroglobulin-deficient mice in models of lethal TNF-induced inflammation.
Tumor necrosis factor (TNF) is an essential mediator in the pathogenesis of Gram-negative septic shock. Injection of TNF into normal mice leads to systemic, lethal inflammation, which is indistinguishable from lipopolysaccharide (LPS)-induced lethal inflammation. alpha(2)-macroglobulin (A2M) is a major positive acute phase protein with broad-spectrum protease-inhibitory activity. Mouse A2M-deficient (MAM-/-) mice were significantly protected against lethal systemic inflammation induced by TNF. The protection is not due to faster clearance of the injected TNF. The induction of tolerance to TNF-induced lethality by repetitive administration of small doses of human TNF for five consecutive days was equally efficient in both mutant mice compared to wild-type mice. In D-(+)-galactosamine (GalN)-sensitized mice, TNF induces lethal inflammatory hepatitis. MAM(-/-) mice are equally sensitive to the lethal combination of TNF/GalN. Furthermore, interleukin-1-induced desensitization to TNF/GalN was not impaired in MAM(-/-) mice. We conclude that MAM plays a mediating role in TNF-induced lethal shock and that MAM deficiency does not reduce changes in efficiency of tolerance and desensitization to TNF and TNF/GalN-induced lethality, respectively.
Hochepied
T
T
Department of Molecular Biology, Flanders Interuniversity for Biotechnonogy, Ghent, Belgium.
Ameloot
P
P
Brouckaert
P
P
Van Leuven
F
F
Libert
C
C
D000818:Animals; D003888:Desensitization, Immunologic; D005688:Galactosamine / Q000494:pharmacology; D006520:Hepatitis, Animal / Q000139:chemically induced; D018836:Inflammation Mediators / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000276:immunology; D012769:Shock / Q000139:chemically induced*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000511:alpha-Macroglobulins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology
D018836:Inflammation Mediators; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000511:alpha-Macroglobulins; D005688:Galactosamine