Lan H Y, Yang N, Metz C, Mu W, Song Q, Nikolic-Paterson D J, Bacher M, Bucala R, Atkins R C
Department of Nephrology, Monash Medical Centre, Victoria, Australia.
Mol Med. 1997 Feb;3(2):136-44.
Macrophage migration inhibitory factor (MIF) is a potent proinflammatory mediator that participates in the pathogenesis of endotoxemia and experimental crescentic glomerulonephritis. However, very little is known about how MIF production is regulated in disease. We therefore examined whether tumor necrosis factor alpha (TNF-alpha), a known inducer of MIF expression by macrophages in vitro, up-regulates local and systemic MIF expression in a macrophage-mediated rat model of crescentic glomerulonephritis.
Anti-glomerular basement membrane (GBM) glomerulonephritis was induced in groups of six primed rats. Animals were treated with 1 mg/kg soluble TNF-alpha receptor (TNFbp) or saline from the time of disease induction until they were killed on Days 1, 7, or 14. Renal MIF expression was assessed by in situ hybridization, immunohistochemistry, and ELISA, and compared with macrophage accumulation and indices of renal damage.
Although TNFbp treatment on Day 1 of the disease had only a partial effect upon the up-regulation of glomerular MIF expression, on Days 7 to 14 it almost completely abrogated the increase in glomerular and interstitial MIF mRNA and protein expression. In addition, TNFbp treatment significantly inhibited MIF secretion by cultured glomeruli and reduced serum MIF levels. The inhibition of renal MIF expression was paralleled by a significant inhibition of glomerular and interstitial macrophage infiltration (p < 0.001 versus saline treated), a significant suppression of renal injury (proteinuria and serum creatinine), and a marked reduction in histologic damage (glomerular hypercellularity, crescent formation, and interstitial fibrosis; all p < 0.01 versus saline treated).
This study demonstrates for the first time that TNF-alpha up-regulates local MIF expression by both infiltrating macrophages and resident kidney cells in rat crescentic glomerulonephritis. In addition, TNF-alpha regulates systemic MIF production. Thus, TNF-alpha, together with MIF, may play a pathological role in immunologically induced renal disease.
巨噬细胞移动抑制因子（MIF）是一种强效促炎介质，参与内毒素血症和实验性新月体性肾小球肾炎的发病机制。然而，关于疾病中MIF产生如何被调控却知之甚少。因此，我们研究了肿瘤坏死因子α（TNF-α），一种已知的体外巨噬细胞MIF表达诱导剂，是否在巨噬细胞介导的新月体性肾小球肾炎大鼠模型中上调局部和全身的MIF表达。
对每组6只致敏大鼠诱导抗肾小球基底膜（GBM）肾小球肾炎。从疾病诱导时起，动物用1mg/kg可溶性TNF-α受体（TNFbp）或生理盐水处理，直至在第1、7或14天处死。通过原位杂交、免疫组织化学和酶联免疫吸附测定评估肾脏MIF表达，并与巨噬细胞积聚和肾损伤指标进行比较。
虽然疾病第1天给予TNFbp处理对肾小球MIF表达上调仅有部分作用，但在第7至14天，它几乎完全消除了肾小球和间质MIF mRNA及蛋白表达的增加。此外，TNFbp处理显著抑制培养肾小球的MIF分泌并降低血清MIF水平。肾脏MIF表达的抑制与肾小球和间质巨噬细胞浸润的显著抑制（与生理盐水处理组相比，p<0.001）、肾损伤（蛋白尿和血清肌酐）的显著抑制以及组织学损伤（肾小球细胞增多、新月体形成和间质纤维化；与生理盐水处理组相比，所有p<0.01）的明显减轻同时出现。
本研究首次证明TNF-α在大鼠新月体性肾小球肾炎中通过浸润的巨噬细胞和肾固有细胞上调局部MIF表达。此外，TNF-α调节全身MIF产生。因此，TNF-α与MIF一起可能在免疫性诱导的肾脏疾病中发挥病理作用。
