Fetuin (alpha2-HS-glycoprotein) opsonizes cationic macrophagedeactivating molecules.
Macrophages become activated by bacterial endotoxin (lipopolysaccharide) and other stimuli to release proinflammatory cytokines and NO. To prevent release of toxic or potentially lethal quantities of these factors, the state of macrophage activation is counter-regulated by anti-inflammatory mediators (e.g., glucocorticoid hormones, interleukin 10, and transforming growth factor type beta). Fetuin, a negative acute-phase protein, recently was implicated as an anti-inflammatory 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 mitogen-activated protein kinase phosphorylation. Fetuin dose-dependently increases macrophage uptake of CNI-1493, which can be specifically inhibited by anti-human fetuin antibodies. Anti-human fetuin antibodies render primary human peripheral blood mononuclear cells insensitive to deactivation by CNI-1493. Thus, macrophages use fetuin as an opsonin for cationic-deactivating molecules, both endogenous (e.g., spermine) and pharmacologic (e.g., CNI-1493). This role of fetuin as an opsonic participant in macrophage-deactivating mechanisms has implications for understanding and manipulating the innate immune response.
Wang
H
H
Department of Emergency Medicine, North Shore University Hospital-New York University School of Medicine, Manhasset, NY 11030, USA. hwang@picower.edu
Zhang
M
M
Bianchi
M
M
Sherry
B
B
Sama
A
A
Tracey
K J
KJ
D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D002852:Chromatography, Ion Exchange; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000493:pharmacokinetics / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D009895:Opsonin Proteins; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification; D014462:Ultrafiltration; D000509:alpha-Fetoproteins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases; D000813:Anilides; D006146:Guanidines
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D006835:Hydrazones; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D009895:Opsonin Proteins; D010446:Peptide Fragments; D000509:alpha-Fetoproteins; D048051:p38 Mitogen-Activated Protein Kinases; C097256:semapimod; D000813:Anilides; D006146:Guanidines