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

Eur Cytokine Netw. 2002 Jan-Mar;13(1):86-91.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Temperature
  • Colony Count, Microbial
  • Disease Susceptibility / metabolism
  • Endotoxins
  • Genetic Predisposition to Disease
  • Gram-Negative Bacterial Infections / genetics
  • Gram-Negative Bacterial Infections / metabolism*
  • Immunity, Innate / genetics
  • Immunity, Innate / physiology*
  • Interleukin-6 / blood
  • Klebsiella pneumoniae
  • Macroglobulins / deficiency
  • Macroglobulins / genetics
  • Macroglobulins / metabolism*
  • Mice
  • Mice, Inbred C57BL / genetics
  • Mice, Knockout / microbiology
  • Sepsis*
  • Shock, Septic / genetics
  • Shock, Septic / metabolism*
  • Survival Rate

Substances

  • Endotoxins
  • Interleukin-6
  • Macroglobulins