FETUIN (ALPHA(2)-HS-GLYCOPROTEIN) OPSONIZES CATIONIC MACROPHAGE-DEACTIVATING MOLECULES

Macrophages become activated by bacterial endotoxin (lipopolysaccharid e) and other stimuli to release proinflammatory cytokines and NO. To p revent release of toxic or potentially lethal quantities of these fact ors, the state of macrophage activation is counter-regulated by anti-i nflammatory mediators (e.g., glucocorticoid hormones, interleukin 10, and transforming growth factor type beta), Fetuin, a negative acute-ph ase protein, recently was implicated as an antiinflammatory mediator, because it is required for macrophage deactivation by spermine, In the present studies, we found that fetuin is necessary for macrophages to respond to CNI-1493, a tetravalent guanylhydrazone inhibitor of p38 m itogen-activated protein kinase phosphorylation, Fetuin dose-dependent ly increases macrophage uptake of CNI-1493, which can be specifically inhibited by anti-human fetuin antibodies. Anti-human fetuin antibodie s render primary human peripheral blood mononuclear cells insensitive to deactivation by CNI-1493. Thus, macrophages use fetuin as an opsoni n for cationic-deactivating molecules, both endogenous (e.g., spermine ) and pharmacologic (e.g., CNI-1493), This role of fetuin as an opsoni c participant in macrophage-deactivating mechanisms has implications f or understanding and manipulating the innate immune response.