Higher Macrophage Migration Inhibitory Factor Levels Research Articles

Macrophage migration inhibitory factor expression is increased in pituitary adenoma cell nuclei.

Macrophage migration inhibitory factor (MIF) is an essential regulator of the macrophage responses to endotoxin. MIF also has the ability to override the anti-inflammatory actions of glucocorticoids during an immune response, and is thus an important pro-inflammatory factor. The presence of MIF in cells of the anterior pituitary has been described, and high levels of MIF in other rapidly proliferating tIssues have also been demonstrated. It has been hypothesised that MIF release from these cells is influenced by the hypothalamo-pituitary-adrenal axis, and that ACTH and MIF are released simultaneously to exert counter-regulatory effects on cortisol. However, another intracellular role for MIF has also been suggested as it has been shown that MIF exerts an effect on the inhibitory cell cycle control protein p27 through an interaction with Jab1, a protein implicated in p27 degradation. We studied MIF expression in different normal and adenomatous human pituitary samples using immunohistochemistry and RT-PCR. There was evidence of co-immunoprecipitation of MIF with Jab1, suggesting an interaction of the two proteins. Our results showed that there is increased expression of MIF protein in the nuclei of all pituitary adenomas compared with normal tIssue (P=0.0067), but there was no statistically significant difference in nuclear MIF expression between the different adenoma types. Nuclear MIF expression correlated positively with p27 and its phosphorylated form in normal tIssue (P=0.0028 and P<0.0001); however, this relationship was not seen in the adenoma samples. Cytoplasmic expression of MIF was found to be variable both in normal and adenomatous samples, with no consistent pattern. MIF mRNA was demonstrated to be present in all tumour and normal samples studied. Somatotroph tumours showed higher MIF mRNA expression compared with normal pituitary or other types of adenomas. In conclusion, MIF is expressed in cell nuclei in pituitary adenomas to a greater extent than in normal pituitary tIssue. We speculate that it may play a role in the control of the cell cycle, but whether its higher level in adenomas is a cause or a consequence of the tumorigenic process remains to be clarified.

Macrophage Migration Inhibitory Factor and Host Innate Immune Responses to Microbes

Among innate immune cells, macrophages play an essential role in the sensing and elimination of invasive microorganisms. Binding of microbial products to pathogen-recognition receptors stimulates macrophages to release cytokines and other effector molecules that orchestrate the host innate and adaptive immune responses. Recently, the protein known as macrophage migration inhibitory factor (MIF) has emerged as a pivotal mediator of innate immunity. First identified as a T-cell cytokine, MIF was rediscovered as a protein released by pituitary cells after exposure to endotoxin [lipopolysaccharide (LPS)] or bacteria and in response to stress. Monocytes, macrophages and lymphocytes constitutively express MIF, which is rapidly released after stimulation with bacterial endotoxins and exotoxins, and cytokines. MIF induces powerful proinflammatory biological responses and has been shown to be an important effector molecule of septic shock. High levels of MIF have been detected in the circulation of patients with severe sepsis and septic shock. Inhibition of MIF activity with neutralizing anti-MIF antibodies or deletion of the Mif gene led to a marked reduction in cytokine production and protected mice from lethal bacterial sepsis and toxic shock induced by Gram-negative endotoxin or Gram-positive exotoxins. Investigations into the mechanisms whereby MIF modulates innate immune responses to endotoxin and Gram-negative bacteria have shown that MIF up-regulates the expression of Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex. Thus, MIF enables cells, such as the macrophage, that are at the forefront of the host antimicrobial defences, to sense promptly the presence of invading Gram-negative bacteria and mount an innate immune response. Given that it is a pivotal regulator of innate immune responses to bacterial infections, MIF appears to be a perfect target for novel therapeutic interventions in patients with severe sepsis.

Macrophage migration inhibitory factor in hepatocellular carcinoma and liver cirrhosis; relevance to pathogenesis

The levels of macrophage migration inhibitory factor (MIF), a proinflammatory and carcinogenic cytokine, were significantly higher in the sera from patients with hepatocellular carcinoma (HCC; 25.6±15.3 ng/ml, n=55) and liver cirrhosis (LC; 18.9±10.7 ng/ml, n=26) compared with sera from patients with gastrointestinal cancer (6.8±7.5 ng/ml, n=29) and normal controls (5.6±1.2 ng/ml, n=45; P<0.01). Hepatocytes from patients with LC and HCC, but not from chronic hepatitis, expressed very high levels of MIF. A possible association between overexpression of MIF and hepatocarcinogenesis is suggested.

Macrophage migration inhibitory factor (MIF) in bronchial asthma

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine favouring the secretion of TNFalpha and IL-8 and counteracts anti-inflammatory effects of corticosteroids. Airways inflammation is a central feature of bronchial asthma and is characterized by the accumulation of eosinophils. The aim of this study was to investigate whether MIF is related to asthma symptoms and eosinophil accumulation in the airways. Serum MIF levels were measured by an enzyme-linked immunosorbent assay in 44 healthy subjects and 44 asthmatics. Levels of MIF in induced sputum were measured in 10 healthy subjects and 15 asthmatics. Levels of eosinophil cationic protein (ECP) in induced sputum were measured by a radioimmunosorbent assay. Fluorescence double immunostaining was conducted to examine cellular source and localization of MIF. Serum MIF levels were significantly increased in asthmatic patients compared with age and sex-matched control subjects. Symptomatic patients had a higher MIF level than asymptomatic patients. Induced sputum obtained from asthmatics contained higher levels of MIF than those from control subjects. MIF levels in induced sputum were correlated with ECP levels in induced sputum. MIF was colocalized with eosinophil peroxidase staining in the cytoplasm of sputum cells. Increased MIF levels are associated with asthma symptoms and one of the cellular sources of MIF in the airways are eosinophils.