Mazumder B, Mukhopadhyay C K, Prok A, Cathcart M K, Fox P L
Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.
J Immunol. 1997 Aug 15;159(4):1938-44.
Ceruloplasmin is a 132-kDa glycoprotein abundant in human plasma. It has multiple in vitro activities, including copper transport, lipid pro- and antioxidant activity, and oxidation of ferrous ion and aromatic amines; however, its physiologic role is uncertain. Although ceruloplasmin is synthesized primarily by the liver in adult humans, production by cells of monocytic origin has been reported. We here show that IFN-gamma is a potent inducer of ceruloplasmin synthesis by monocytic cells. Activation of human monoblastic leukemia U937 cells with IFN-gamma increased the production of ceruloplasmin by at least 20-fold. The identity of the protein was confirmed by plasmin fingerprinting. IFN-gamma also increased ceruloplasmin mRNA. Induction followed a 2- to 4-h lag and was partially blocked by cycloheximide, indicating a requirement for newly synthesized factors. Ceruloplasmin induction in monocytic cells was agonist specific, as IL-1, IL-4, IL-6, IFN-alpha, IFN-beta, TNF-alpha, and LPS were completely ineffective. The induction was also cell type specific, as IFN-gamma did not induce ceruloplasmin synthesis in endothelial or smooth muscle cells. In contrast, IFN-gamma was stimulatory in other monocytic cells, including THP-1 cells and human peripheral blood monocytes, and also in HepG2 cells. Ceruloplasmin secreted by IFN-gamma-stimulated U937 cells had ferroxidase activity and was, in fact, the only secreted protein with this activity. Monocytic cell-derived ceruloplasmin may contribute to defense responses via its ferroxidase activity, which may drive iron homeostasis in a direction unfavorable to invasive organisms.
铜蓝蛋白是一种在人血浆中含量丰富的132 kDa糖蛋白。它具有多种体外活性，包括铜转运、脂质促氧化和抗氧化活性以及亚铁离子和芳香胺的氧化；然而，其生理作用尚不确定。虽然铜蓝蛋白主要由成年人体内的肝脏合成，但也有报道称单核细胞来源的细胞可产生铜蓝蛋白。我们在此表明，γ干扰素是单核细胞合成铜蓝蛋白的有效诱导剂。用γ干扰素激活人单核细胞白血病U937细胞可使铜蓝蛋白的产量增加至少20倍。通过纤溶酶指纹图谱证实了该蛋白的身份。γ干扰素还增加了铜蓝蛋白mRNA的表达。诱导作用有2至4小时的延迟，并被环己酰亚胺部分阻断，这表明需要新合成的因子。单核细胞中铜蓝蛋白的诱导是激动剂特异性的，因为白细胞介素-1、白细胞介素-4、白细胞介素-6、α干扰素、β干扰素、肿瘤坏死因子-α和脂多糖完全无效。这种诱导也是细胞类型特异性的，因为γ干扰素不会在内皮细胞或平滑肌细胞中诱导铜蓝蛋白的合成。相比之下，γ干扰素在其他单核细胞中具有刺激作用，包括THP-1细胞和人外周血单核细胞，在HepG2细胞中也有刺激作用。γ干扰素刺激的U937细胞分泌的铜蓝蛋白具有亚铁氧化酶活性，实际上是唯一具有这种活性的分泌蛋白。单核细胞来源的铜蓝蛋白可能通过其亚铁氧化酶活性有助于防御反应，这可能会使铁稳态朝着不利于侵袭性生物体的方向发展。
