Wang H, Zhang M, Bianchi M, Sherry B, Sama A, Tracey K J
Department of Emergency Medicine, North Shore University Hospital-New York University School of Medicine, Manhasset, NY 11030, USA.
Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14429-34. doi: 10.1073/pnas.95.24.14429.
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.
巨噬细胞可被细菌内毒素（脂多糖）和其他刺激物激活，从而释放促炎细胞因子和一氧化氮。为防止这些因子释放出有毒或可能致命的量，巨噬细胞的激活状态会受到抗炎介质（如糖皮质激素、白细胞介素10和转化生长因子β）的反向调节。胎球蛋白是一种负急性期蛋白，最近被认为是一种抗炎介质，因为精胺使巨噬细胞失活需要它。在本研究中，我们发现胎球蛋白是巨噬细胞对CNI-1493（一种p38丝裂原活化蛋白激酶磷酸化的四价胍腙抑制剂）作出反应所必需的。胎球蛋白剂量依赖性地增加巨噬细胞对CNI-1493的摄取，抗人胎球蛋白抗体可特异性抑制这种摄取。抗人胎球蛋白抗体使原代人外周血单核细胞对CNI-1493的失活作用不敏感。因此，巨噬细胞将胎球蛋白用作内源性（如精胺）和药理学（如CNI-1493）阳离子失活分子的调理素。胎球蛋白作为调理素参与巨噬细胞失活机制这一作用，对于理解和调控天然免疫反应具有重要意义。
