Bootcov M R, Bauskin A R, Valenzuela S M, Moore A G, Bansal M, He X Y, Zhang H P, Donnellan M, Mahler S, Pryor K, Walsh B J, Nicholson R C, Fairlie W D, Por S B, Robbins J M, Breit S N
Centre for Immunology, St. Vincent's Hospital, and University of New South Wales, Sydney, 2010, Australia.
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11514-9. doi: 10.1073/pnas.94.21.11514.
Macrophages play a key role in both normal and pathological processes involving immune and inflammatory responses, to a large extent through their capacity to secrete a wide range of biologically active molecules. To identify some of these as yet not characterized molecules, we have used a subtraction cloning approach designed to identify genes expressed in association with macrophage activation. One of these genes, designated macrophage inhibitory cytokine 1 (MIC-1), encodes a protein that bears the structural characteristics of a transforming growth factor beta (TGF-beta) superfamily cytokine. Although it belongs to this superfamily, it has no strong homology to existing families, indicating that it is a divergent member that may represent the first of a new family within this grouping. Expression of MIC-1 mRNA in monocytoid cells is up-regulated by a variety of stimuli associated with activation, including interleukin 1beta, tumor necrosis factor alpha (TNF-alpha), interleukin 2, and macrophage colony-stimulating factor but not interferon gamma, or lipopolysaccharide (LPS). Its expression is also increased by TGF-beta. Expression of MIC-1 in CHO cells results in the proteolytic cleavage of the propeptide and secretion of a cysteine-rich dimeric protein of Mr 25 kDa. Purified recombinant MIC-1 is able to inhibit lipopolysaccharide -induced macrophage TNF-alpha production, suggesting that MIC-1 acts in macrophages as an autocrine regulatory molecule. Its production in response to secreted proinflammatory cytokines and TGF-beta may serve to limit the later phases of macrophage activation.
巨噬细胞在涉及免疫和炎症反应的正常及病理过程中发挥关键作用，这在很大程度上是通过其分泌多种生物活性分子的能力来实现的。为了鉴定其中一些尚未被表征的分子，我们采用了一种消减克隆方法，旨在鉴定与巨噬细胞激活相关表达的基因。其中一个基因，命名为巨噬细胞抑制性细胞因子1（MIC-1），编码一种具有转化生长因子β（TGF-β）超家族细胞因子结构特征的蛋白质。尽管它属于这个超家族，但与现有家族没有很强的同源性，这表明它是一个分化成员，可能代表该组内一个新家族中的首个成员。单核细胞样细胞中MIC-1 mRNA的表达可被多种与激活相关的刺激上调，包括白细胞介素1β、肿瘤坏死因子α（TNF-α）、白细胞介素2和巨噬细胞集落刺激因子，但不包括干扰素γ或脂多糖（LPS）。TGF-β也可增加其表达。MIC-1在CHO细胞中的表达导致前肽的蛋白水解切割并分泌出一种25 kDa的富含半胱氨酸的二聚体蛋白。纯化的重组MIC-1能够抑制脂多糖诱导的巨噬细胞TNF-α产生，这表明MIC-1在巨噬细胞中作为一种自分泌调节分子发挥作用。其对分泌的促炎细胞因子和TGF-β的反应性产生可能有助于限制巨噬细胞激活的后期阶段。
