类风湿关节炎中的巨噬细胞移动抑制因子：促炎功能及糖皮质激素调节的证据

Macrophage migration inhibitory factor in rheumatoid arthritis: evidence of proinflammatory function and regulation by glucocorticoids.

作者信息

Leech M, Metz C, Hall P, Hutchinson P, Gianis K, Smith M, Weedon H, Holdsworth S R, Bucala R, Morand E F

机构信息

Monash Medical Centre, Melbourne, Australia.

出版信息

Arthritis Rheum. 1999 Aug;42(8):1601-8. doi: 10.1002/1529-0131(199908)42:8<1601::AID-ANR6>3.0.CO;2-B.

DOI:10.1002/1529-0131(199908)42:8<1601::AID-ANR6>3.0.CO;2-B

PMID:10446857

Abstract

OBJECTIVE

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine whose involvement in tumor necrosis factor alpha (TNFalpha) synthesis and T cell activation suggests a role in the pathogenesis of rheumatoid arthritis (RA). Antagonism of MIF is associated with marked inhibition of animal models of RA. Uniquely, MIF is inducible by low concentrations of glucocorticoids. We sought to investigate the expression of MIF in RA synovial tissue.

METHODS

MIF was demonstrated in human RA synovium by immunohistochemistry, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and reverse transcription-polymerase chain reaction (RT-PCR). Regulation of MIF expression was investigated by treatment of cultured fibroblast-like synoviocytes (FLS) with interleukin-1beta (IL-1beta), TNFalpha, or interferon-gamma (IFNgamma), and dexamethasone (DEX). Mononuclear cell TNFalpha release after exposure to FLS-conditioned medium was measured by ELISA.

RESULTS

MIF was present in RA synovial lining CD14+ macrophages and FLS. Constitutive MIF messenger RNA (mRNA) expression was demonstrated by RT-PCR of RNA from unstimulated cultured RA FLS, which also released abundant MIF. Serum, synovial fluid, and FLS intracellular MIF were significantly higher in RA patients than in controls. Synoviocyte MIF was not increased by IL-1beta, TNFalpha, or IFNgamma. In contrast, DEX 10(-7)M significantly reduced synoviocyte MIF, while DEX 10(-10)-10(-12)M induced a significant increase in MIF and MIF mRNA. Peripheral blood mononuclear cell TNFalpha release was induced by culture in RA FLS-conditioned medium, and this induction was significantly abrogated by monoclonal anti-MIF antibody, suggesting that MIF is an upstream regulator of TNFalpha release.

CONCLUSION

These data represent the first demonstration of the cytokine MIF in human autoimmune disease and suggest MIF as a potential therapeutic target in RA.

摘要

目的

巨噬细胞移动抑制因子（MIF）是一种促炎细胞因子，它参与肿瘤坏死因子α（TNFα）的合成以及T细胞的激活，提示其在类风湿关节炎（RA）发病机制中发挥作用。MIF拮抗作用与RA动物模型的显著抑制相关。独特的是，低浓度糖皮质激素可诱导MIF产生。我们试图研究MIF在RA滑膜组织中的表达情况。

方法

通过免疫组织化学、流式细胞术、酶联免疫吸附测定（ELISA）以及逆转录-聚合酶链反应（RT-PCR）检测人RA滑膜组织中的MIF。通过用白细胞介素-1β（IL-1β）、TNFα、干扰素-γ（IFNγ）或地塞米松（DEX）处理培养的成纤维样滑膜细胞（FLS）来研究MIF表达的调节。通过ELISA测定暴露于FLS条件培养基后单核细胞TNFα的释放量。

结果

MIF存在于RA滑膜衬里的CD14+巨噬细胞和FLS中。通过对未刺激的培养RA FLS的RNA进行RT-PCR证实了MIF信使核糖核酸（mRNA）的组成性表达，这些FLS也释放大量MIF。RA患者的血清、滑液和FLS细胞内的MIF显著高于对照组。IL-1β、TNFα或IFNγ未使滑膜细胞MIF增加。相反，10^(-7)M的DEX显著降低滑膜细胞MIF，而10^(-10)-10^(-12)M的DEX诱导MIF和MIF mRNA显著增加。在RA FLS条件培养基中培养可诱导外周血单核细胞TNFα释放，而单克隆抗MIF抗体可显著消除这种诱导作用，提示MIF是TNFα释放的上游调节因子。