Fetuin (α₂-HS-glycoprotein) opsonizes cationic macrophagedeactivating molecules

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 ␤). Fetuin, a negative acute-phase 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 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.

Multifunctional Roles for Serum Protein Fetuin-A in Inhibition of Human Vascular Smooth Muscle Cell Calcification

“…In support of this, our data and other recent reports show that fetuin-A is important in phagocytosis (39). Fetuin-A has also been shown to inhibit the inflammatory response of macrophages after phagocytosis (40). Efficient phagocytosis may be particularly important in limiting accelerated atherosclerotic calcification in patients with ESRD, which is associated with inflammatory macrophages and cell death, and where AB form the nidus for calcification (39,41,42).…”

Glycoprotein analysis of porcine bronchoalveolar lavage fluid reveals potential biomarkers corresponding to resistance toActinobacillus pleuropneumoniaeinfection

“…Thus, haptoglobin plays a major role as hem binding reactant and its expression is known to increase during the acute phase of A. pleuropneumoniae infections [18]; the significantly decreased haptoglobin levels in chronic diseased animals on day 20 may refer to severe hemolytic processes [54]. Fetuin A inhibits the production of pro-inflammatory cytokines such as IL-1b, TNF-alpha, and NO by participation in macrophage deactivation as opsonin [12,51] and, thereby, participates in preventing excessive immune reactions detrimental to the host.…”

Preeclampsia is associated with decreased serum α2-HS glycoprotein (fetuin-A) concentration

“…55 In addition, AHSG, as an opsonin, was required for macrophage deactivation in vitro. 56 AHSG also attenuated tumor necrosis factor-a synthesis and the innate inflammatory response in an experimental model. 57 Moreover, the protein has been shown to enhance the phagocytosis of apoptotic cells by macrophages.…”