title: Mice lacking alpha(2)-macroglobulin show an increased host defense against Gram-negative bacterial sepsis, but are more susceptible to endotoxic shock.
abstract: The onset of an acute phase response is one of the initial steps in the defense against an infectious organism. Alpha(2)-macroglobulin (alpha(2)M), an acute phase protein in most mammalian species, is known to have a broad antiprotease activity, but it can also bind a number of growth factors, cytokines, ions and lipid factors. We have shown that alpha(2)M-deficient (MAM-/-) mice are more resistant to a lethal Gram-negative infection compared to control mice. This increased resistance was reflected in significantly higher body temperatures, compared to control mice, during the infection as well as in a prolonged and increased survival. Moreover, the clearance of bacteria in MAM-/- mice was significantly more efficient than in control mice. On the other hand, MAM-/- mice were more susceptible to endotoxin. An LD(100) challenge with endotoxin in MAM-/- mice was not lethal for control mice. Our data suggest that alpha(2)M plays a dual role during an acute phase response. In the establishment of a lethal Gram-negative infection, leading to sepsis and septic shock, it has a mediating role by hampering the efficient clearance of bacteria. During endotoxic shock, however, alpha(2)M has a rather protective function.
authors.affiliation: Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, Ghent University, KL Ledeganckstraat 35, B-9000 Ghent, Belgium.
authors.forename: Tino
authors.initials: T
authors.lastname: Hochepied
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
mesh_terms: D000818:Animals; D001831:Body Temperature; D015169:Colony Count, Microbial; D004198:Disease Susceptibility / Q000378:metabolism; D004731:Endotoxins; D020022:Genetic Predisposition to Disease; D016905:Gram-Negative Bacterial Infections / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D015850:Interleukin-6 / Q000097:blood; D007711:Klebsiella pneumoniae; D008259:Macroglobulins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D018345:Mice, Knockout / Q000382:microbiology; D018805:Sepsis; D012772:Shock, Septic / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D004731:Endotoxins; D015850:Interleukin-6; D008259:Macroglobulins