INDUCTION OF MN SOD IN HUMAN MONOCYTES WITHOUT INFLAMMATORY CYTOKINE PRODUCTION BY A MUTANT ENDOTOXIN

Endotoxin selectively induces monocyte Mn superoxide dismutase (SOD) w ithout affecting levels of Cu,Zn SOD, catalase, or glutathione peroxid ase. However, little is known about the structure-activity relationshi p and the mechanism by which endotoxin induces Mn SOD. In this study w e demonstrated that a mutant Escherichia coli endotoxin lacking myrist oyl fatty acid at the 3' R-3-hydroxymyristate position of the lipid A moiety retained its full capacity to coagulate Limulus amoebocyte lysa te compared with the wild-type E. coli endotoxin and markedly stimulat ed the activation of human monocyte nuclear factor-kappa B and the ind uction of Mn SOD mRNA and enzyme activity. However, in contrast to the wild-type endotoxin, it failed to induce significant production of tu mor necrosis factor-a: and macrophage inflammatory protein-1 alpha by monocytes and did not induce the phosphorylation and nuclear transloca tion of mitogen-activated protein kinase. These results suggest that 1 ) lipid A myristoyl fatty acid, although it is important for the induc tion of inflammatory cytokine production by human monocytes, is not ne cessary for the induction of Mn SOD, 2) endotoxin-mediated induction o f Mn SOD and inflammatory cytokines are regulated, at least in part, t hrough different signal transduction pathways, and 3) failure of the m utant endotoxin to induce tumor necrosis factor-a production is, at le ast in part, due to its inability to activate mitogen-activated protei n kinase.