Expression of macrophage migration inhibitory factor in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis

AIM AND METHODS: To investigate the relationship between macrophage migration inhibitory factor and clinical or pathological findings in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody MPO-ANCA-associated glomerulonephritis characterized by idiopathic necrotizing crescentic glomerulonephritis, renal biopsy specimens from 16 patients with MPO-ANCA-associated glomerulonephritis and 15 controls were stained using an enzyme antibody method to detect macrophage migration inhibitory factor and macrophages infiltrating the glomeruli. The relationship of this factor with various clinical parameters and with cellular crescents was determined. RESULTS: Macrophage migration inhibitory factor was detected in 11 out of 16 patients with MPO-ANCA-associated glomerulonephritis, but was not found in any of the controls. In the positive patients, the blood MPO-ANCA level was significantly higher than in the negative patients. Both cellular crescents and the number of macrophages infiltrating the glomeruli were significantly increased in the patients positive for macrophage migration inhibitory factor. CONCLUSION: Thus, macrophage migration inhibitory factor may be closely related to cellular crescent formation and disease activity in patients with MPO-ANCA-associated glomerulonephritis.     

巨噬细胞移动抑制因子在原发性肾小球肾炎肾脏组织中的表达及其意义

目的 研究巨噬细胞移动抑制因子（MIF）在原发性肾小球肾炎患者肾脏组织中的表达水平及其与巨噬细胞浸润、肾脏病理改变、肾功能损害的相关关系。方法 正常人和原发性肾小球肾炎患者肾组织MIF蛋白、巨噬细胞标记抗原（抗CD68,KPI）的检测应用微波免疫组织化学染色方法检测;MIF的基因表达应用原位杂交方法;MIF与KP1的相关关系应用免疫组织化学双标记技术检测。肾脏组织的病理改变应用常规病理学方法检测。24h尿蛋白、血肌酐的测定按本院检验科常规方法检测。结果 正常人肾脏组织仅有少量MIF的表达,原发性肾小球肾炎患者肾脏组织MIF表达水平（包括蛋白和mRNA）显著上调。原发性肾小球肾炎患者肾组织MIF表达水平与KP1^ 细胞数有显著相关性,MIF表达水平、MIF^ KP1^ 细胞数与肾脏病理改变程度及肾功能损害明显相关。结论 MIF在原发性肾小球肾炎患者肾脏组织的表达水平显著上调;并与肾脏组织巨噬细胞浸润、肾脏病理改变程度、肾功能损害密切相关,提示MIF表达水平显著上调可能是原发性肾小球肾炎患者肾损害的重要机制之一。     

周围神经损伤后巨噬细胞游走抑制因子mRNA在许旺细胞的表达状况

目的　探讨周围神经损伤后 ,许旺细胞表达巨噬细胞游走抑制因子 (macrophagemigrationinhibitoryfactor,MIF)mRNA的变化 ,明确许旺细胞及MIF在激活巨噬细胞、促进神经再生中的作用。　方法　取 50只大鼠 ,随机分为 1 0组 ,每组 5只。 1组设为正常对照组 ,其余 9组分别在预损伤坐骨神经后 1、1 2h及 1、3、7、1 0、1 4、1 7、2 1d ,分离纯化许旺细胞 ,提取RNA。采用半定量RT PCR法检测RNA的水平。经图像分析测出正常及各预损伤组MIFmRNA的相对水平。　结果　许旺细胞中MIFmRNA的表达量在神经损伤后 1 2h开始出现明显升高 (0 342 0± 0 0 0 2 6) ;伤后 7d达到最高(0 6388± 0 0 0 2 0 )后 ,维持在较高水平 ;至伤后 1 0d(0 6397± 0 0 0 2 3)开始缓慢下降 ;2 1d(0 2 76 4±0 0 0 2 7)后恢复至伤前水平。　结论　周围神经损伤后 ,许旺细胞及其所分泌的MIF在巨噬细胞聚集激活过程中可能起着重要作用     

巨噬细胞移动抑制因子在狼疮性肾炎中的作用

目的了解狼疮性肾炎肾组织巨噬细胞移动抑制因子（ＭＩＦ）的表达及其与肾脏病理和功能损害的关系。方法采用微波免疫组化双重染色的方法，观察正常肾和狼疮肾组织ＭＩＦ表达及狼疮肾皮质ＭＩＦ＋、小鼠抗人ＣＤ６８抗体（Ｋｐ１＋）、ＭＩＦ＋Ｋｐ１＋细胞数与狼疮肾组织活动指数、肾脏组织功能损害的关系。结果狼疮性肾炎肾组织ＭＩＦ表达较正常组明显增多、增强，狼疮组肾组织ＭＩＦ＋、Ｋｐ１＋、ＭＩＦ＋Ｋｐ１＋细胞数与狼疮肾组织活动指数、肾脏病理和功能损害明显相关。结论ＭＩＦ在介导狼疮性肾炎病损中起重要作用，其上调表达可作为反映狼疮肾活动及进行性肾损害的指标。     

巨噬细胞移动抑制因子与消化管肿瘤的相关性研究进展

巨噬细胞移动抑制因子(macrophage migration inhibitory factor,MIF)是一种具有多向性生物学行为的细胞因子.随着对MIF的分子生物学及其临床研究的深入,发现MIF与消化管肿瘤的增殖与侵袭有着密切的关系.本文就MIF与消化管肿瘤的关系进行综述.     

巨噬细胞移动抑制因子在男性生殖方面的研究进展

巨噬细胞移动抑制因子（MIF）是一种具有广泛组织分布和多种生物学功能的小分子蛋白质。研究表明,MIF在男性生殖系统中以特异的生物学功能影响精子的发生和成熟。了解男性生殖系统中MIF对精子发生、成熟的影响及相关分子生物学机制,有助于临床男性不育分子水平的诊疗。本文就近年来MIF在男性生殖系统中的合成及影响精子发生的特异性生物学功能以及相关机制的进展做一综述。     

Systemic macrophage migration inhibitory factor release following hepatic resection

We set out to determine the responses of macrophage migration inhibitory factor (MIF) to hepatic resection and investigate its role in predicting short-term postoperative morbidity and outcome. Blood samples from 29 patients undergoing hepatic resection and eight healthy volunteers were obtained serially for 24 h and assayed for serum MIF, cortisol, and tumor necrosis factor (TNF)-α. The MIF and cortisol levels showed a parallel increase and their peak levels were significantly correlated (r ² = 0.33, P = 0.0011). The TNF-α levels also increased during and after hepatic resection, but did not correlate with the MIF levels. The patients were classified into an extended hepatectomy group (n = 9); a lobectomy/segmentectomy group (n = 12); and a subsegmentectomy group (n = 8). There were no differences in the time courses of MIF (P = 0.8699), cortisol (P = 0.7485), and TNF-α (P = 0.3819) among the three groups. No patients developed organ dysfunction and all were discharged from the intensive care unit without any complications. Our findings demonstrate that MIF production occurs in patients undergoing hepatic resection. Surgical stress may play a more important role in MIF secretion than inflammatory stimulus by TNF-α in these patients. Therefore, MIF minimally affects short-term postoperative morbidity and outcome. Received: March 1, 2000 / Accepted: November 20, 2000     

Lung-derived macrophage migration inhibitory factor in sepsis induces cardio-circulatory depression

BACKGROUND: Acute lung injury is common during sepsis. Whereas gaseous exchange often can be supported adequately, death results frequently from cardio-circulatory depression, the mechanisms of which remain unclear. The aim of this study was to determine whether cardio-circulatory dysfunction during sepsis results from release of macrophage migration inhibitory factor (MIF) by the lung. METHODS: Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in adult Sprague-Dawley rats. Macrophage MIF was measured in the plasma sampled from the right ventricle (pre-lung) and left atrium (post-lung). RESULTS: The concentration of macrophage MIF in each of the post-lung samples was higher than in the corresponding pre-lung sample at 6 h (p = 0.015; paired t-test), 20 h (p = 0.008), and 30 h (p = 0.026) after the induction of sepsis. Next, rats that underwent CLP were treated with either saline (control) or our specific MIF inhibitor, (S, R )-3-(4-hydroxyphenyl)-4,5-dehydro-5-isoxazole acetic acid methyl ester (ISO-1). Echocardiography revealed that ISO-1 significantly improved the left ventricular end-diastolic volume index (p = 0.02), stroke volume index (p = 0.01), and cardiac index (p = 0.02) at 30 h after the induction of sepsis. CONCLUSIONS: The lung appears to release significant amounts of macrophage MIF into the systemic circulation during late sepsis. Inhibition of MIF in a clinically relevant time frame blocked polymicrobial peritonitis-induced cardio-circulatory dysfunction. Inhibition of MIF may be a useful strategy to prevent cardio-circulatory deterioration associated with late sepsis.     

Cardiac allograft rejection in the absence of macrophage migration inhibitory factor

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a secreted proinflammatory lymphokine essential for elicitation of delayed-type hypersensitivity (DTH) reactions in vivo. We tested whether MIF blockade-absence affected acute or chronic murine cardiac allograft rejection. METHODS: Wild-type (WT) C57BL/6 (B6) mice underwent transplantation with BALB/c hearts with or without blocking anti-MIF antibody, and MIF knockout (KO) B6 mice underwent transplantation with MIF KO BALB/c hearts. Chronic immune injury was induced in WT and KO recipients using donor-specific transfusion and anti-CD40L antibody. RESULTS: Unexpectedly, the blockade or genetic absence of MIF did not prolong graft survival even if recipient T-cell cytotoxicity was additionally impaired. The histologic manifestations of acute and chronic immune injury to the allograft were similar between groups. CONCLUSIONS: MIF is not required for acute or chronic allograft rejection in mice. The findings raise questions about the role of DTH as an important mediator of cardiac allograft injury.     

Urinary macrophage migration inhibitory factor in children with urinary tract infection

Macrophage migration inhibitory factor (MIF) plays an essential pathophysiological role in inflammatory reactions. The aim of this study was to investigate the clinical utility of urine MIF (uMIF) level in predicting urinary tract infections (UTI). This multicenter, prospective study was conducted over a 1-year period between March 2008 and March 2009. Sixty patients with symptomatic culture-proven UTI and 29 healthy children were recruited. Urine MIF was measured by enzyme-linked immunosorbent assay. The mean MIF level was found to be significantly higher in the UTI group than in the control group (1082.82 vs. 211.45 pg/ml, p?=?0.0001). Receiver operating characteristic (ROC) analysis revealed that the optimal cut-off uMIF level was 295 pg/ml for uMIF to predict UTI. The sensitivity and specificity of this cut-off level were 91.7% and 69%, respectively. Mean uMIF/creatinine (Cr) was also significantly higher in the UTI group than in the control group (2400.69 vs. 267.56 pg/mgCr, p?=?0.0001). At a cut-off of 815 pg/mgCr for uMIF/Cr, the sensitivity and specificity were 95 and 79%, respectively. The area under curve (AUC) was 0.848 (standard error 0.040, 95% confidence interval 0.756–0.915) for uMIF and 0.889 (0.034, 0.805–0.946) for uMIF/Cr. Urine MIF/Cr was significantly higher in the patients with a positive leukocyte esterase reaction in the urine (p?=?0.047), leukocytosis (p?=?0.0001) and positive C-reactive protein level in serum (p?=?0.003). The uMIF level was not related to leukocytosis, positive CRP level in serum and leukocyte esterase reaction in the urine. Neither uMIF nor uMIF/Cr were correlated to the positive urine nitrite test, pyuria, urine pH and specific gravity (p?>?0.05). These results suggest that urine MIF and uMIF/Cr can be used for the early prediction of UTI in children.     

Macrophage migration inhibitory factor is increased in the urine of patients with urinary tract infection: macrophage migration inhibitory factor-protein complexes in human urine

PURPOSE: MIF is a proinflammatory cytokine present in preformed stores in human urothelium. In animal models of bladder inflammation, including bacterial cystitis, MIF is up-regulated in the bladder and released from the bladder as a high molecular weight complex. We compared urine MIF amounts in patients with UTI to that in patients without UTI, and we examined and identified MIF-protein complexes in urine. MATERIALS AND METHODS: Using enzyme-linked immunosorbent assay we compared MIF levels in the urine of 14 patients with UTI to levels in 16 controls with no UTI. Western blotting under native, denaturing and reducing conditions was done to examine MIF complexes found in urine. Mass spectrometry identified MIF associated proteins in urine, while co-immunoprecipitation confirmed the associations. RESULTS: Mean urine MIF amounts +/- SEM determined by enzyme-linked immunosorbent assay were significantly greater in 14 patients with UTI compared to that in 16 controls (1.96 +/- 0.40 vs 0.59 +/- 0.09 ng/mg creatinine, p <0.01). Western blotting under denaturing conditions showed several high molecular weight complexes (100 to 165 kDa) that increased in UTI urine as well as typical, monomeric MIF (12 kDa). Mass spectrometry identified associated MIF proteins, including ceruloplasmin, albumin and uromodulin. Co-immunoprecipitation confirmed mass spectrometry findings and also identified MIF interaction with alpha-2-macroglobulin. CONCLUSIONS: Increased urine MIF amounts in patients with bacterial cystitis support our experimental evidence showing a role for MIF in pelvic visceral inflammation. The novel finding of an association of MIF with other urine proteins suggest that the physiologically relevant form of MIF may be an MIF-protein complex.     

巨噬细胞移动抑制因子在肝癌诊断中的价值

目的 探讨巨噬细胞移动抑制因子(MIF)在肝癌诊断中的价值.方法 试验分为测试研究和验证研究.回顾性分析2004年1月至5月复旦大学附属中山医院收治的269例肝癌患者(测试肝癌组)和390例对照人群(测试对照组);8月至12月收治的173例肝癌患者(验证肝癌组)和257例对照人群(验证对照组);2005年1月收治的80例行根治性肝切除的肝癌患者的临床资料.收集测试研究和验证研究受试者术前体格检查的血浆标本和行根治性肝切除的肝癌患者术前、术后3、7、30 d的血浆标本,同时收集测试肝癌组患者术后的肝癌组织和癌旁(距肿瘤1cm)组织标本.采用ELISA法检测血浆中MIF水平,免疫组织化学法检测组织中MIF表达情况.非正态分布数据用中位数(四分位数间距)[M(QR)]表示,组间比较采用Mann-Whitney U检验,血浆和组织中MIF的关系采用Spearman相关分析,ROC曲线分析MIF的诊断价值.结果 在测试研究中,测试肝癌组和测试对照组受试者血浆MIF中位值分别为85.7 μg/L(58.8 μg/L)和15.5 μg/L(31.6 μg/L).其中测试对照组中的肝硬化患者、良性肝病患者和健康体检者血浆MIF中位值分别为24.9 μg/L( 12.6 μg/L)、12.5 μg/L(7.3μg/L)、13.2 μg/L(7.7 μg/L),两组各受试者血浆MIF比较,差异有统计学意义(F=54.235,P＜0.05).ROC曲线结果表明,当血浆MIF为35.3 μg/L时,可获得最大的曲线下面积.验证肝癌组与验证对照组比较,AUC值、灵敏度、特异度分别为92.1％、90.7％、93.4％.肝癌患者术前和术后3、7、30 d血浆MIF中位值分别为81.0μg/L(54.0μg/L)、76.1 μg/L(47.5 μg/L)、50.9 μg/L(40.7 μg/L)、18.7μg/L(15.1 μg/L),呈时间依赖性降低,术后30 d基本恢复到正常范围内.肝癌组织和癌旁组织MIF的中位表达强度分别为0.083和0.007,两者比较,差异有统计学意义(U=3.975,P＜0.05).肝癌患者血浆中MIF和相应的肝癌组织内MIF表达呈正相关(r=0.759,P＜0.05).结论 MIF与肝癌发生、发展密切相关,MIF可作为肝癌诊断的潜在分子标志物.     

Urinary levels of macrophage migration inhibitory factor in patients with IgA nephropathy

BACKGROUND/AIM: The processes involved in development of IgA nephropathy (IgAN) are not yet well understood. Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine and is an essential component of immune and inflammatory responses. To examine further the possible role of MIF in IgAN, we measured MIF levels in the urine. The purpose of the present study was to evaluate the involvement of MIF in IgAN. METHODS: Urine samples were obtained from 20 IgAN patients. The disease controls included 20 patients with minimal-change nephrotic syndrome (MCNS). A group of healthy subjects served as control. The samples were assayed for MIF protein by a sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The MIF levels in the urine of patients with IgAN examined were significantly higher than those of the healthy control subjects. In contrast, the levels of urinary MIF (uMIF) in patients with MCNS did not differ significantly from normal values. In IgAN patients, uMIF significantly correlated with the magnitude of proteinuria, but not with the grade of hematuria. We also investigated the relationship between uMIF levels and pathological features. Among patients with IgAN, uMIF levels were significantly correlated with the grade of glomerular crescent formation and that of mesangial cell proliferation. There was also a significant correlation between uMIF levels and the number of both intraglomerular and interstitial macrophages. CONCLUSION: Although the underlying mechanisms remain to be determined, these data provide evidence that urinary excretion of MIF is increased in IgAN patients with active renal lesions.     

Urine macrophage migration inhibitory factor concentrations as a diagnostic tool in human renal allograft rejection.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is a potent activator of macrophages and T cells. Previous studies have shown that local MIF production is increased in acute renal allograft rejection, suggesting that it may play an important role in the rejection process. AIMS: To determine if urine and serum MIF concentrations: (1) are increased in acute rejection, and (2) can be used as noninvasive tools to discriminate between acute rejection (AR) and cyclosporine nephrotoxicity (CyA toxicity). METHODS: In a prospective study of nine renal allograft patients (five acute rejection and four stable), serial urine MIF concentrations were measured by ELISA in the first 14 days after transplantation. In a retrospective study, MIF concentrations in urine and serum were measured in 24 patients who were biopsied for acute renal transplant dysfunction (11 AR, 13 CyA toxicity). Urine and serum MIF were also measured in 23 stable renal transplant patients and 10 normals. RESULTS: MIF was readily detected in the urine of normal healthy controls (106+/-61 pg/micromol creatinine). In the prospective study, the urinary MIF concentration was increased substantially on day 1 posttransplantation and subsequently fell in parallel with the serum creatinine. However, urine MIF increased before episodes of biopsy proven acute rejection. The retrospective study showed that urine MIF concentrations in patients with AR were increased 5-fold compared to normal controls (439+/-313 pg/micromol Cr; P<0.01). In contrast, urine MIF concentrations in CyA toxicity were not significantly different to normal controls (145+/-119 pg/micromol Cr; P=NS). A marked increase in MIF immunostaining was seen in biopsies of AR, but not in CyA toxicity. No significant differences were evident in serum MIF levels between normals and any transplant patient group. CONCLUSIONS: These results suggest that measurement of urine MIF concentration may be useful in monitoring renal transplant patients for acute rejection and as a discriminator from cyclosporine nephrotoxicity.     

巨噬细胞移动抑制因子在大鼠急性坏死性胰腺炎模型中的作用研究

目的初步探讨巨噬细胞移动抑制因子（MIF）在大鼠急性坏死性胰腺炎（ANP）发病中的作用。方法健康雄性SD大鼠60只,随机分成三组,分别为对照组（腹腔注射生理盐水）、ANP组（腹腔注射左旋精氨酸）和干预组（腹腔注射左旋精氨酸＋单克隆抗MIF抗体）,每组20只。采用左旋精氨酸改良方法建立ANP模型,分别于3、6、12、24h四个不同时点处死5只大鼠,剖腹后从肠系膜上静脉取血,ELISA法测定血清MIF、TNF-α、IL-1、IL-6和IL-8水平 碘比法测定血淀粉酶 切取胰腺组织依据Kusske标准行胰腺病理学评分 Western blot法测定胰腺组织NF-κBp65蛋白的表达。结果ANP组血淀粉酶及胰腺组织病理学评分各时点㈦对照组相比均显著升高,干预组㈦ANP组相比均显著降低（P〈0.01） 胰腺组织NF-κBp65蛋白的表达于造模后3h开始呈持续性上调,与对照组相比其表达显著增多,在干预组其表达水平㈦ANP组相比明显下调（P〈0.01） 血清MIF、TNF-α、IL-1、IL-6各时点在ANP组与正常对照组相比其水平均有明显升高,在干预组其水平㈦ANP组相比显著降低（P〈0.05） 血清IL-8在6、12、24h不同时点水平变化同上述因子,但在3h时点其水平无明显升高 MIF、胰腺组织病理学评分及胰腺组织NF-κBp65蛋白的表达,两两之间均成正相关（P〈0.05）。结论腹腔注射左旋精氨酸建立ANP的模型是稳定的 MIF可能通过调控核因子NF-κB的途径影响血清TNF-α、IL-1、IL-6及IL-8水平而在大鼠急性胰腺炎发病过程中起一定的作用。     

Change of macrophage migration inhibitory factor: Possible indicator for postoperative prognosis

Sixty three cancer cases who received minimum of the removal of the main tumor constitute the subjects of the present study. Macrophage migration inhibitory factor (MIF) of peripheral blood lymphocytes was studied using extirpated autochthonous tumor tissues as antigen and guinea-pig peritoneal exudative cells as indicator cells immediately before the operation and the fourth postoperative week. The results indicated that in those cases of relatively early stage, i.e. Stages I and II, whose tumor was believed to have been removed completely, MIF turned negative in 7/9 (77.8 per cent) after the operation, while in others with advanced cancer of Stage IV in which the tumor bearing tissue was probably not completely removed, MIF turned positive in most cases (13/17: 75.6 per cent) postoperatively, even though it was negative before the operation. In the cases of Stage III with cancer progressed to an intermediate degree, in about half of the cases (7/11: 63.6 per cent) MIF turned negative after the operation and in the other half (7/10: 70 per cent) MIF became positive postoperatively, suggesting that for MIF to persist the presence of certain amount of tumor tissue is necessary. Supported by Grant No. 077230 in Aid for Scientific Research from the Ministry of Education of Japan.     

Polymeric IgA increases the synthesis of macrophage migration inhibitory factor by human mesangial cells in IgA nephropathy.

BACKGROUND: It has been suggested that polymeric IgA (pIgA) or IgA immune complexes play a significant pathogenic role in IgA nephropathy (IgAN). Macrophage migration inhibitory factor (MIF) shares many activities with other pro-inflammatory cytokines. In human glomerulonephritis, including IgAN, glomerular expression of MIF is found to correlate with progressive renal injury. We hypothesized that deposition of pIgA within the kidney may lead to enhanced synthesis of MIF by mesangial cells. METHODS: In this study we examined the effect of pIgA and monomeric IgA (mIgA) from randomly selected patients with IgAN in clinical quiescence on the gene expression and protein synthesis of MIF in cultured human mesangial cells (HMC). RESULTS: Both pIgA and mIgA from IgAN patients or matched healthy controls increased MIF gene expression and protein synthesis in a dose-dependent fashion. The magnitude of MIF protein induction by pIgA (100 microg/ml) was similar to that of tumour necrosis factor-alpha (TNF-alpha) at 10 pg/ml. In all subjects, the induction of MIF was higher for pIgA when compared with mIgA (P < 0.01). Furthermore, the up-regulation of MIF synthesis by either pIgA or mIgA was significantly higher in IgAN patients than in healthy controls (P < 0.05). Similarly, pIgA and mIgA were able to induce TNF-alpha gene expression and protein synthesis in mesangial cells. Incubation of mesangial cells with neutralizing antibody to TNF-alpha reduced the MIF synthesis induced by pIgA. CONCLUSION: We demonstrate that pIgA is capable of inducing MIF and TNF-alpha production in HMC, which may play a major pathogenic role in IgAN. Induction of MIF can be partially blocked by neutralizing antibody to TNF-alpha, suggesting the possibility that up-regulation of MIF synthesis in HMC is mediated via an amplifying proinflammatory loop involving TNF-alpha.     

巨噬细胞移动抑制因子基因启动子区CATT微卫星多态性与脓毒症发生发展的相关性

巨噬细胞移动抑制因子(macrophagemigrationin hibitoryfactor,MIF)是一种主要的前炎因子,在脓毒症、急性呼吸窘迫综合征等炎症性疾病的发生发展中起着重要的作用[1]。Bozza等[2]研究观察到,外科大手术后机体血浆中MIF的水平与脓毒症的发生、预后密切相关。MIF基因启动子区-794