Mice lacking alpha(2)-macroglobulin show an increased host defense against Gram-negative bacterial sepsis, but are more susceptible to endotoxic shock.

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.