Differential response of alpha(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 sys temic, lethal inflammation, which is indistinguishable from lipopolysacchar ide (LPS)-induced lethal inflammation. alpha (2)-macroglobulin (A2M) is a m ajor positive acute phase protein with broad-spectrum protease-inhibitory a ctivity. Mouse A2M-deficient (MAM(-/-)) mice were significantly protected a gainst lethal systemic inflammation induced by TNF, The protection is not d ue to faster clearance of the injected TNF, The induction of tolerance to T NF-induced lethality by repetitive administration of small doses of human T NF for five consecutive days was equally efficient in both mutant mice comp ared 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-l-induced des ensitization to TNF/GalN was not impaired in MAM(-/-) mice. We conclude tha t MAM plays a mediating role in TNF-induced lethal shock and that MAM defic iency does not reduce changes in efficiency of tolerance and desensitizatio n to TNF and TNF/GalN-induced lethality, respectively.