Increased Macrophage Migration Inhibitory Factor Expression Research Articles

Gastric Epithelial Expression of Macrophage Migration Inhibitory Factor is not Altered by Helicobacter pylori Infection in Humans

Recent reports have shown an upregulation of macrophage migration inhibitory factor (MIF) during gastric ulcer development in a rat model and elevated counts of MIF-positive cells in biopsies from Helicobacter pylori-infected patients. H. pylori infection is a proven cofactor in humans causing gastritis and gastric ulcers. The aim of this study was to characterize MIF expression in human gastric epithelial cells in response to H. pylori. MIF mRNA and MIF protein expression was detected in human gastric epithelial cell lines after stimulation with proinflammatory cytokines or infection with H. pylori (cagA+/vacA+) using real-time reverse transcriptase-polymerase and enzyme-linked immunosorbent assay. Interleukin-8 secretion was measured as positive control. MIF mRNA and MIF protein expression was assessed in H. pylori-positive and -negative human gastric biopsy samples. While interleukin-8 mRNA expression and interleukin-8 secretion were upregulated in gastric epithelial cells in vitro after H. pylori infection, no changes in MIF mRNA expression and MIF secretion could be detected. We found no significant differences in MIF expression in total RNA extracted from gastric biopsy tissue when comparing H. pylori-positive to control patients. Likewise, MIF protein expression in gastric epithelium was unaffected by H. pylori infection as compared to uninfected tissue. While an increased MIF expression and positive effects of MIF blockade in ulcer healing have been shown in a rodent model and elevated numbers of MIF-positive cells have been found in H. pylori-infected human tissue, we herein could not confirm any differences in human gastric epithelial MIF expression and secretion after H. pylori infection in vitro and in vivo.

Upregulation of macrophage migration inhibitory factor contributes to induced N-Myc expression by the activation of ERK signaling pathway and increased expression of interleukin-8 and VEGF in neuroblastoma.

Macrophage migration inhibitory factor (MIF) has been linked to fundamental processes such as control of cell proliferation, cell survival, angiogenesis, and tumor progression. The expression of MIF has been reported in several tumors. However, the precise role of MIF in tumor cells remains unclear. In the present study, we investigated the expression pattern and the function of MIF in neuroblastoma. Our results showed that intracellular MIF was upregulated in neuroblastoma tumor tissues and cell lines. MIF protein expression significantly correlated with the grade of tumor differentiation. In addition, we found that MIF induced a significant dose-dependent increase of vascular endothelial growth factor and interleukin-8 secretion. We also observed that an increased MIF expression level correlated with N-Myc protein (the N-myc oncogene product) expression in neuroblastoma tissues. MIF increased the expression of N-myc mRNA and N-Myc protein and induced N-Myc translocation from the cytoplasm to nucleus in neuroblastoma cell lines. MIF-induced N-Myc expression was found to be dependent on ERK signaling pathways. The inhibition of ERK activation reduced MIF-mediated N-Myc expression. These results suggest that MIF may contribute to the progression of neuroblastoma by (a) inducing N-Myc expression and (b) upregulating the expression of angiogenic factors.

Macrophage migration inhibitory factor evaluation compared with prostate specific antigen as a biomarker in patients with prostate carcinoma.

Cytokines are polypeptides that constitute a class of chemical mediator molecules that modulate cell growth by inducing specific target gene expression. The objective of this study was to evaluate the clinical usefulness of serum evaluation of the cytokine macrophage migration inhibitory factor (MIF) in patients undergoing routine prostate specific antigen (PSA) screening. In this preliminary, retrospective study, the authors report the development of an enzyme-linked immunosorbent assay (ELISA) for MIF determination in serum samples. A polymerase chain reaction (PCR)-based assay investigated associations between MIF expression and prostate carcinoma (CaP). The authors developed a relative quantitative reverse transcriptase-PCR assay to determine MIF mRNA amounts within laser-capture microscopy (LCM)-dissected prostate epithelial cells. A comparison of serum MIF levels and total PSA levels identified a positive correlation (correlation coefficient [r2] = 0.61; P < 0.001; n = 509 patients), suggesting an association between elevated serum concentrations of these proteins and CaP. A correlation of serum MIF levels with a diagnosis of CaP demonstrated that patients with a previous CaP diagnosis had significantly elevated serum MIF concentrations (mean +/- standard deviation, 6.8 +/- 0.87 ng/mL; P < 0.001). To associate altered serum MIF levels with MIF mRNA expression within prostate epithelial cells, LCM-dissected prostate epithelial cells (formalin fixed biopsies from three different patients) were used to determine MIF mRNA amounts by PCR analysis. On average, MIF mRNA amounts were 6.5 times higher in CaP epithelial cells that were invasive to the margin compared with MIF mRNA amounts in normal prostate epithelial cells within the same biopsy specimen. The ELISA data from the current study suggested an association between increased MIF expression and CaP and suggested that serum MIF concentration may serve as a prognostic marker for CaP.

Macrophage migration inhibitory factor expression in human renal allograft rejection.

Macrophage migration inhibitory factor (MIF) plays a pivotal role in immune-mediated diseases. Despite the long-standing association of MIF with the delayed-type hypersensitivity response, the potential role of MIF in allograft rejection is unknown. MIF expression was assessed by in situ hybridization and immunohistochemistry staining in 62 biopsies of human renal allograft rejection and in normal human kidney. MIF mRNA and protein is constitutively expressed in normal kidney, being largely restricted to tubular epithelial cells, some glomerular epithelial cells, and vascular smooth muscle cells. In both acute and chronic renal allograft rejection, there was marked up-regulation of MIF mRNA and protein expression by intrinsic kidney cells such as tubular epithelial cells and vascular endothelial and smooth muscle cells. There was also MIF expression by infiltrating macrophages and T cells. Of note, macrophage and T cell infiltrates were largely restricted to areas with marked up-regulation of MIF expression, potentially contributing to the development of severe tubulitis and intimal or transmural arteritis. Quantitative analysis found that increased MIF expression in allograft rejection gave a highly significant correlation with macrophage and T cell accumulation in both the glomerulus and interstitium (P<0.001). In addition, the number of MIF+ tubules and interstitial MIF+ cells correlated significantly with the severity of allograft rejection (P<0.01), and the loss of renal function (P<0.01). In contrast, no up-regulation of renal MIF expression and no leukocyte accumulation was seen in allograft biopsies without evidence of rejection. This is the first study to demonstrate that local MIF expression is up-regulated during allograft rejection. The association between up-regulation of MIF expression, macrophage and T cell infiltration and the severity of renal allograft rejection suggests that MIF may be an important mediator in the process of allograft rejection.