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Fetuin (alpha2-HS-glycoprotein) opsonizes cationic macrophagedeactivating molecules
1Department of Emergency Medicine, North Shore University Hospital-New York University School of Medicine, Manhasset, NY 11030, USA. hwang@picower.edu
Abstract:
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.
Insights
Fetuin acts as an opsonin, helping macrophages internalize anti-inflammatory molecules like CNI-1493. This mechanism is crucial for regulating macrophage deactivation and the innate immune response.
Area of Science:
- Immunology
- Cell Biology
Background:
- Macrophages release pro-inflammatory cytokines and nitric oxide (NO) upon activation by stimuli like lipopolysaccharide.
- Anti-inflammatory mediators, including glucocorticoids and interleukin 10, counteract excessive macrophage activation.
- Fetuin, a negative acute-phase protein, was previously identified as essential for spermine-mediated macrophage deactivation.
Purpose of the Study:
- To investigate the role of fetuin in the deactivation of macrophages by CNI-1493, a p38 mitogen-activated protein kinase inhibitor.
- To elucidate the mechanism by which fetuin facilitates the uptake of deactivating molecules by macrophages.
Main Methods:
- Assessed the necessity of fetuin for macrophage response to CNI-1493.
- Quantified the effect of fetuin on CNI-1493 uptake by macrophages.
- Utilized anti-human fetuin antibodies to inhibit fetuin-mediated uptake and assess its impact on CNI-1493 deactivation in human peripheral blood mononuclear cells.
Main Results:
- Fetuin is essential for macrophages to respond to CNI-1493.
- Fetuin dose-dependently enhances macrophage uptake of CNI-1493, an effect blocked by anti-fetuin antibodies.
- Anti-fetuin antibodies prevent CNI-1493-induced deactivation of human peripheral blood mononuclear cells.
Conclusions:
- Macrophages utilize fetuin as an opsonin for cationic anti-inflammatory molecules, including endogenous spermine and the pharmacologic agent CNI-1493.
- Fetuin's function as an opsonin in macrophage deactivation provides insights into modulating innate immune responses.