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JA Baugh
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SC Donnelly
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The diverse actions of macrophage migration inhibitory factor (MIF) within the immuno-neuroendocrine system are yet to be fully understood, but it is clear that MIF plays a pivotal role in the regulation of both the innate and adaptive immune response. An emerging body of data presently indicates that MIF's position within the cytokine cascade is to act in concert with glucocorticoids to control the 'set point' and magnitude of the immune and inflammatory response. In this article we will review the actions of MIF within the immune system and discuss the overlapping and contrasting aspects of MIF and glucocorticoid biology. In particular we will focus on the role of MIF within the immuno-neuroendocrine interface and suggest molecular mechanisms by which MIF may counter-regulate glucocorticoid function. Finally we will discuss emerging evidence that functional MIF gene-promoter polymorphisms render one susceptible to elevated MIF expression, and the development of an exaggerated immune/inflammatory response that potentiates the progression to chronic inflammatory disease.

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YO Lukyanenko
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AM Carpenter
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DE Brigham
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DM Stocco
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JC Hutson
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The purpose of this investigation was to study the mechanism of action of a macrophage-derived factor that stimulates steroid production by Leydig cells. This factor increased testosterone production within 30 min, and reached a half-maximal response by 6-8 h. At a maximal dose, it stimulated testosterone production 20-fold at 24 h. Its efficacy was consistently higher than that achieved with a maximal dose of human chorionic gonadotropin (hCG). However, Leydig cells treated with a maximal dose of both the macrophage-derived factor and hCG secreted the same amount of testosterone as when given a maximal dose of only the macrophage-derived factor. The macrophage-derived factor did not require new protein synthesis to stimulate testosterone production, nor did it alter the amount of steroidogenic acute regulatory protein (StAR). While the macrophage-derived factor required an active cholesterol side-chain cleavage complex system, it did not alter the capacity of this enzyme complex. Finally, the macrophage-derived factor was unable to stimulate the production of progesterone by isolated mitochondria. In summary, the macrophage-derived factor is a highly active, acute regulator of steroidogenesis that acts through a high capacity StAR-independent pathway.

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L Oziol
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P Faure
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N Bertrand
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P Chomard
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Oxidized low density lipoproteins (LDL) are highly suspected of initiating the atherosclerosis process. Thyroid hormones and structural analogues have been reported to protect LDL from lipid peroxidation induced by Cu2+ or the free radical generator 2,2'-azobis-'2-amidinopropane' dihydrochloride in vitro. We have examined the effects of thyroid compounds on macrophage-induced LDL oxidation. Human monocyte-derived macrophages (differentiated U937 cells) were incubated for 24 h with LDL and different concentrations (0-20 microM) of 3,5,3'-triiodo-l -thyronine (T3), 3,5,3',5'-tetraiodo-L-thyronine (T4), 3,3',5'-tri-iodo-l -thyronine (rT3), the T3 acetic derivative (3,5,3'-tri-iodothyroacetic acid; TA3) or L-thyronine (T0) (experiment 1). Cells were also preincubated for 24 h with 1 or 10 microM of the compounds, washed twice, then incubated again for 24 h with LDL (experiment 2). Oxidation was evaluated by measurement of thiobarbituric acid-reactive substances (TBARS) and cell viability by lactate deshydrogenase release. In experiment 1, T0 had no effect, whereas the other compounds decreased LDL TBARS production, but T3 and TA3 were less active than T4 and rT3 (IC50: 11.0 +/- 2.6 and 8.1 +/- 0.8 vs 1.4 +/- 0.5 and 0.9 +/- 0.3 microM respectively). In experiment 2, the compounds at 1 microM had no effect; at 10 microM, T3 and rT3 slightly reduced LDL TBARS production, whereas TA3 and T4 inhibited it by about 50% and 70% respectively. TBARS released by the cells were also highly decreased by T3, T4, rT3 and TA3 in experiment 1, but only by T3 (30%) and T4 (70%) in experiment 2. Cell viability was not affected by the compounds except slightly by TA3 at 10 microM. The data suggested that the physico-chemical antioxidant capacity of thyroid compounds was modulated by their action on the intracellular redox systems of macrophage. Overall cellular effects of T3 led to a reduction of its antioxidant capacity whereas those of T4 increased it. Thus T4 might protect LDL against cellular oxidation in vivo more than T3.

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ME Pyle
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M Korbonits
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M Gueorguiev
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S Jordan
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B Kola
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DG Morris
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A Meinhardt
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MP Powell
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FX Claret
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Q Zhang
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C Metz
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R Bucala
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AB Grossman
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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.

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RP Donn
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DW Ray
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The immunological and neuroendocrine properties of macrophage migration inhibitory factor (MIF) are diverse. In this article we review the known cellular, molecular and genetic properties of MIF that place it as a key regulatory cytokine, acting within both the innate and adaptive immune responses.The unexpected and paradoxical induction of MIF secretion by low concentrations of glucocorticoids is explored. The role of MIF as a locally acting modulator of glucocorticoid sensitivity within foci of inflammation is also discussed. MIF has no homology with any other pro-inflammatory cytokine and until recently lacked a recognised transmembrane receptor. MIF has also been shown to be directly taken up into target cells and to interact with intracellular signalling molecules, including the Jun activation domain-binding protein Jab-1.Comprehensive analysis of the MIF gene has identified important functional polymorphisms and a series of genetic studies has revealed both association and linkage of MIF with inflammatory diseases. Altered MIF regulation may therefore be pivotal to acquiring chronic inflammation following an innate immune response.

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SJ Heasman
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KM Giles
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C Ward
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AG Rossi
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C Haslett
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I Dransfield
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Glucocorticoids represent one of the most effective clinical treatments for a range of inflammatory conditions, including severe acute inflammation. Although glucocorticoids are known to affect processes involved in the initiation of inflammation, the influence of glucocorticoids on the mechanisms by which acute inflammation normally resolves have received less attention. Apoptosis of granulocytes present at inflamed sites leads to their rapid recognition and internalisation by macrophages, a process which may be important for resolution of inflammation. However, if clearance of either eosinophils or neutrophils is impaired, these cells rapidly undergo secondary necrosis leading to release of pro-inflammatory mediators from the phagocyte, potentially prolonging inflammatory responses. Physiologically relevant concentrations of glucocorticoids accelerate eosinophil apoptosis whilst delaying neutrophil apoptosis during in vitro culture. Here we discuss key pathways regulating the granulocyte apoptotic programme and summarise the effects of glucocorticoids on monocyte differentiation and the consequent changes to apoptotic cell clearance capacity. Definition of the mechanisms underlying resolution of inflammatory responses following glucocorticoid treatment may unveil new targets for modulation of inflammatory disease, allowing co-ordinated augmentation of granulocyte apoptosis together with increased macrophage capacity for clearance of apoptotic cells.

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Qiongge Zhang Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China

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Chaoqun Wang Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China

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Yehua Tang Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai, China

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Qiangqiang Zhu Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China

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Yongcheng Li Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China

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Haiyan Chen Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China

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Yi Bao Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China

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Song Xue Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China

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Liangliang Sun Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China

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Wei Tang Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China

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Xiangfang Chen Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China

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Yongquan Shi Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China

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Lefeng Qu Department of Vascular and Endovascular Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China

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Bin Lu Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China

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Jiaoyang Zheng Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China

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recognized as a proinflammatory and pro-atherogenic cytokine ( Cho et al. 2009 , Wolak 2014 ). In the progress of atherosclerosis, OPN have been shown to be highly expressed in macrophages, vascular smooth muscle cells (VSMCs) and endothelial cells (ECs

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L E Nicol Pediatrics, Division of Neurosciences, Pape Pediatric Research Institute

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W R Grant Pediatrics, Division of Neurosciences, Pape Pediatric Research Institute

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S M Comstock Pediatrics, Division of Neurosciences, Pape Pediatric Research Institute

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M L Nguyen Pediatrics, Division of Neurosciences, Pape Pediatric Research Institute

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M S Smith Pediatrics, Division of Neurosciences, Pape Pediatric Research Institute

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K L Grove Pediatrics, Division of Neurosciences, Pape Pediatric Research Institute

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D L Marks Pediatrics, Division of Neurosciences, Pape Pediatric Research Institute
Pediatrics, Division of Neurosciences, Pape Pediatric Research Institute

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Monisha Rajasekaran Department of Biological Sciences, University of Ulsan, Ulsan, Korea

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Ok-Joo Sul Department of Biological Sciences, University of Ulsan, Ulsan, Korea

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Eun-Kyung Choi Department of Biological Sciences, University of Ulsan, Ulsan, Korea

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Ji-Eun Kim Department of Biological Sciences, University of Ulsan, Ulsan, Korea

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Jae-Hee Suh Department of Pathology, Ulsan University Hospital, Ulsan, Korea

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Hye-Seon Choi Department of Biological Sciences, University of Ulsan, Ulsan, Korea

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act in an adipocyte-autonomous way, whereas others are mediated by macrophage polarization. Macrophages can obtain distinct functional phenotypes, M1 and M2, via different polarization responses to environmental stimuli. M1 phenotypes are stimulated

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