Macrophage migration inhibitory factor (MIF) exhibits a pronounced circadian rhythm relevant to its role as a glucocorticoid counter-regulator

Autoimmunity Research Unit, The Canberra Hospital, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Immunology and Cell Biology (Impact Factor: 4.15). 05/2003; 81(2):137-43. DOI: 10.1046/j.0818-9641.2002.01148.x
Source: PubMed


In humans, maximal expression of T helper 1 cytokines coincide with the nocturnal nadir of plasma cortisol, whereas T helper 2 cytokine responses are dominant during day-time. The pro-inflammatory cytokine, macrophage migration inhibitory factor counter-regulates glucocorticoid-mediated immune suppression. To determine the relationship between cortisol and macrophage migration inhibitory factor, healthy volunteers had blood drawn hourly for 24 h for measurement of plasma cortisol and basal- and stimulated-macrophage migration inhibitory factor. Similar to cortisol, macrophage migration inhibitory factor peaked during the late morning whereas interferon-gamma, tumour necrosis factor-alpha, interleukin-1 and interleukin-12 demonstrated a nocturnal peak. After oral cortisone, plasma macrophage migration inhibitory factor rose 2-4-fold, whereas the other cytokines decreased. There was no correlation between cortisol during the insulin tolerance test and plasma macrophage migration inhibitory factor. The late morning peak of macrophage migration inhibitory factor, by antagonizing cortisol-mediated pro-inflammatory cytokine suppression may prolong the duration of early morning inflammation. These observations explain the beneficial role of macrophage migration inhibitory factor neutralization in models of inflammatory arthritis.

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Available from: Nikolai Petrovsky, Sep 04, 2014
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    • "MIF's close association with the HPA axis, as well as glucocorticoid regulation more generally, makes it a compelling biomarker for inflammatory activity among maltreated youth. Similar to diurnal cycles of cortisol, MIF levels exhibit a circadian rhythm, with levels fluctuating between 2 and 6 ng/ml, and peak levels evident 2–3 hr in advance, possibly reflecting its role in serving as a glucocorticoid counter-regulator (Petrovsky et al., 2003). Animal studies find that MIF is expressed and released at all levels of the HPA axis including the hypothalamus, the pituitary gland (whereby it is released by the same pituitary cell types that release ACTH; (Bernhagen et al., 1993; Nishino et al., 1995b), and the adrenal glands (Bacher et al., 1997; Tampanaru-Sarmesiu et al., 1997). "
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    ABSTRACT: The study examined Hypothalamus-Pituitary-Adrenal (HPA) axis and inflammatory signaling in 206 youth with histories of prenatal drug exposure and self-reported histories of maltreatment. Youth with histories of severe neglect showed elevated levels of cortisol, the end product of the HPA axis, in comparison to youth with lower or minimal levels of neglect. Histories of severe neglect also were associated with increased levels of Macrophage Migration Inhibitory Factor (MIF), a cytokine known to be intricately involved in HPA axis regulation. Salivary MIF levels also were positively associated with youth age and prenatal drug exposure. These MIF and cortisol alterations may signal pathophysiological disruptions in the neuro-endocrine and immune systems, which may lead to trajectories of increased disease risk among vulnerable youth. Our findings also provide preliminary support for the validity and reliability of a noninvasive salivary assessment of MIF. © 2014 Wiley Periodicals, Inc. Dev Psychobiol.
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    • "The other "late" proinflammatory molecule, MIF normally circulates at low levels of 2-10 ng/mL [38]. Plasma MIF concentration increases during infection and very high levels have been found in cases with severe sepsis and septic shock [39]. "
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    • "This protein is ubiquitously expressed in various organs, such as the brain and kidney. Among cytokines, MIF is unique in terms of its abundant expression and storage within the cytoplasm and, further, for its counteraction against glucocorticoids [4] [5]. MIF has unexpectedly been found to convert d-dopachrome, an enantiomer of naturally occurring l-dopachrome, to 5,6-dihydroxyindole [6]. "
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    ABSTRACT: Recent research suggested the involvement of migration inhibitor factor (MIF) in cancer and inflammatory diseases, which prompted several attempts to develop new MIF inhibitors. Accordingly, we investigated the pharmacophoric space of 79 MIF inhibitors using seven diverse subsets of inhibitors to identify plausible binding hypotheses (pharmacophores). Subsequently, we implemented genetic algorithm and multiple linear regression analysis to select optimal combination of pharmacophores and physicochemical descriptors capable of explaining bioactivity variation within the training compounds (QSAR model, r63=0.62, F=42.8, rLOO(2)=0.721,rPRESS(2) against 16 external test inhibitors=0.58). Two orthogonal pharmacophores appeared in the optimal QSAR model suggestive of at least two binding modes available to ligands inside MIF binding pocket. Subsequent validation using receiver operating characteristic (ROC) curves analysis established the validity of these two pharmacophores. We employed these pharmacophoric models and associated QSAR equation to screen the National Cancer Institute (NCI) list of compounds. Eight compounds gave >50% inhibition at 100μM. Two molecules illustrated >75% inhibition at 10μM.
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