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PubMed1991

Effects of melanostatine (MIF-1) on focal potentials in slices of rat brain cortex.

The effects of tripeptide melanostatine (Melano-Inhibitory Factor--MIF-1) in concentrations 10(-7)-10(-5) M on parameters of focal potentials (FPs) were studied in slices of rat olfactory and parietal cortex. The addition of MIF-1 to perfusion fluid caused in olfactory cortex the primary depression of FP amplitudes evoked by stimulation of the lateral olfactory tract (LOT); this depression was replaced by restoration and prolonged (30-40 min) enhancement of FP amplitudes and by appearance of additional FP components, such as disynaptic EPSPs and IPSPs. In parietal cortex slices MIF-1 caused the elevation of FP amplitudes evoked by stimulating adjoining points. The repetitive perfusion of slices with MIF-1 potentiated the peptide effect on the increase of FP amplitudes. During excitatory period MIF-1 influenced specifically the functional plasticity in olfactory cortex, having facilitated the induction and sustaining of post-tetanic potentiation (PTP). Data observed support the idea of the activatory influence of MIF-1 on the CNS at the cellular level, which is likely to lie in the ground of antidepressant properties of this peptide.

Animals↗
PubMed1980

MIF-I suppresses deprivation-induced fluid consumption in rats.

Rats were injected IP with a 0.1 mg/kg dose of MIF-I, naloxone, dynorphin, [D-Phe4]-Met-enkephalin, [D-Ala2, F5Phe4]-Met-enkephalin-NH2, or the diluent vehicle, placed in their home cages for ten minutes, and then given ad lib access to either 20% sucrose, 10% sucrose, water, 0.01% quinine, or 0.02% quinine in a repeated measures design with solutions counter-balanced over five days. Fluid consumption was measured very hour for 4 hours. A mixed analysis of variance yielded significant results for all main effects and the peptides by fluid and hours by fluid interactions. For the 4-hr test period, naloxone and [D-Phe4]-Met-enkephalin produced reliable increased in consumption while MIF-I produced a reliable decrease. Differences were obtained only with sucrose solutions, and the results clearly suggest that peptides modulate fluid consumption at positive levels of incentive motivation. To reconcile the findings of increased consumption after naloxone with the many studies suggesting a decrease in such paradigms, 0.1, 1.0, and 10.0 mg/kg of naloxone and MIF-I were administered as before but to independent groups of rats and intake was measured every 30 min. These results replicate and extend the above findings by showing that during the first 30-min period, both naloxone and MIF-I suppressed intake in a dose-dependent fashion, with MIF-I being more effective at each dose. The 0.1 mg/kg naloxone group, however, increased consumption over time and achieved a total consumption greater than control animals but comparable to that observed in the first study. It appears that at very low doses naloxone increases consumption over time, but at more commonly tested higher doses it has a suppressant effect. The results support the concept that in many situations MIF-I can produce the same effects as naloxone.

Animals↗
PubMed1981

alpha-MSH, MIF-I and melatonin: effects on novelty-induced defecation, plasma 11-OHCS and central catecholamines in rats.

The pituitary-hypothalamo-pineal complex involving MSH, MIF-I and melatonin has been strongly emphasized in the adaptive mechanism of the animal. A series of experiments was conducted to investigate the effects of alpha-MSH, MIF-I and melatonin on novelty-induced defecation, step-down activity, plasma 11-OHCS levels and whole brain DA and NE concentrations over days of novelty X drug treatment. alpha-MSH consistently enhanced and sustained novelty-induced defecation, increased plasma 11-OHCS levels in the resting intact rats and in the novelty exposed hypophysectomized (hypox) rats, and decreased brain DA and NE levels in intact, hypox and sham-hypox rats. MSH did not increase plasma 11-OHCS in intact and sham-hypox rats during exposure to novelty. MIF-I significantly habituated novelty-induced defecation and increased brain DA and NE levels over 5 days of drug X novelty treatment. Melatonin, on the other hand, inhibited novelty-induced defecation, decreased plasma 11-OHCS and increased brain DA level over 5 days of melatonin X novelty treatment. MSH, MIF-I or melatonin did not show any significant effect on the step-down activity of the rats. The results suggest the possibility that central CAs may be implicated in the behavioral changes observed after alpha-MSH, MIF-I and melatonin administration and in the interaction of the pituitary-hypothalamo-pineal complex involving MSH, MIF-I and melatonin.

11-Hydroxycorticosteroids↗
PubMed1981

Effects of MIF-I and sex differences on tonic immobility duration in the lizard, Anolis carolinensis.

In June, 36 lizards (males and females) were injected with 0.01, 0.1, 1.0, 10.0, or 100 mg/kg of MIF-I, or the diluent vehicle, and placed in a cage for ten minutes. Tonic immobility (TI) was then induced on an open lab table. All doses of MIF-I significantly reduced TI duration as compared to the duration with the diluent alone. In subsequent experiments lizards were injected with 0.1 mg/kg of MIF-I, 0.1 mg/kg of naloxone, or the diluent vehicle, and placed in small aquaria for ten minutes. TI was then induced in the small aquaria. In July, using 60 females, MIF-I and naloxone slightly reduced the duration of TI, but not significantly, and overall TI durations were reduced as compared with the first experiment possibly because the lizards could escape from the view of the experimenter in the corners of the aquaria. A third experiment was done in late September and early October with 120 males and 120 females. No drug effect was seen, but there was a significant difference between the TI durations of males and females, the females having longer durations. A relationship between the difference in response to MIF-I and the breeding seasons of the lizards could not be determined due to the possibility that the change in experimental design after the June experiments may alone have accounted for the loss of the significant response to MIF-I.

Animals↗
PubMedDate not supplied

Modification of d-amphetamine- or chlorpromazine-induced hypothermia by beta-endorphin, MIF-I, and alpha-MSH: mediation by the dopaminergic system.

The effects of beta-endorphin, MIF-I, and alpha-MSH on d-amphetamine- a CPZ-induced hypothermias in rats kept at 4 degrees C were tested in three experimental groups: (a) intact; (b) rats with lesions of the olfactory tubercle; and (c) rats in which the link between the DA mesolimbic pathway and the striatum was disconnected. All drugs tested alone (except MIF-I) caused significant hypothermia. Pretreatment with CPZ, MIF-I, and alpha-MSH potentiated d-amphetamine-induced hypothermia in intact rats. Pretreatment with alpha-MSH potentiated CPZ-induced hypothermia. beta-Endorphin partially blocked d-amphetamine-induced hypothermia, but did not interact with CPZ, MIF-I, or alpha-MSH. All potentiations were either reduced or disappeared in the incisioned rats. CPZ and alpha-MSH caused hypothermia in olfactory tubercle-lesioned rats. The results indicate that: (a) the DA mesolimbic pathway is involved in the hypothermic response of all drugs tested; (b) an intact feedback loop is required for the potentiation of the hypothermic response of CPZ on d-amphetamine, MIF-I on d-amphetamine, and alpha-MSH on d-amphetamine and CPZ; (c) beta-endorphin acts as a partial blocker of d-amphetamine; MIF-I is a weak potentiator of d-amphetamine, alpha-MSH acts as a negative modulator of the DA system, most probably in the striatum.

Animals↗
PubMed1983

Tyr-MIF-1 affects passive avoidance behavior but not motor activity in rats.

The effects of the brain peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) were tested with several behavioral tests after peripheral injection in rats. In a passive avoidance test, Tyr-MIF-1 (1 mg/kg SC) resulted in significantly faster entry into the second compartment of a two-chamber shuttle box than was found with MIF-1 or diluent. Tyr-MIF-1 also resulted in flinch and escape responses that occurred at reliably lower amperage than the control. No significant effects were obtained on measures of ambulation, rearing, or defecation. The results demonstrate that Tyr-MIF-1 can affect behavior and that this action can differ from that of the same dose of MIF-1.

Animals↗
PubMed2005

Increased levels of macrophage migration inhibitory factor (MIF) in preeclampsia.

OBJECTIVE: MIF is a proinflammatory cytokine involved in reproduction. Systemic activation of maternal inflammatory cell responses may play an important role in the pathogenesis of preeclampsia (PE). We hypothesized that MIF could be involved in preeclampsia. STUDY DESIGN: Concentration of immunoreactive MIF was assayed by enzyme-linked immunoassorbent assay (ELISA) in maternal serum samples obtained from 41 term control pregnancies and 21 severe preeclamptic pregnancies (14 delivered before and 7 at or after 34 weeks). RESULTS: MIF serum levels were significantly higher in preeclamptic pregnancies (median 12.74 ng/ml) than in control group (median 5.3n g/ml) p = 0.001. MIF concentration was significantly higher when delivery occurred <34 weeks (median 17.80 ng/ml; range 2.80-80.20) than in the group delivered > or = 34 weeks (median 6.16 ng/ml; range 1.62-23.65) p = 0.037. CONCLUSIONS: High maternal serum levels MIF in pregnancies complicated by severe preeclampsia strongly support the role of inflammation in the pathogenesis of this disease.

Female↗
PubMed1999

Augmented expression of macrophage migration inhibitory factor (MIF) in the telencephalon of the developing rat brain.

Macrophage migration inhibitory factor (MIF) has been characterized as a proinflammatory cytokine, hormone, and immunomodulator. We previously demonstrated the distribution of MIF in the adult rat brain and revealed its expression in neurons as well as glial cells. In this study, we investigated the localization of MIF in the developing rat brain from embryonic day (ED) 13 to ED19, and after birth from postnatal day (PD) 1 to PD28 using both immunohistochemistry and in situ hybridization. On ED16, the signals of MIF mRNA were high in the ventricular, subventricular, and intermediate zones of the telencephalon, in which 'neuropoietic' progenitor cells proliferate and migrate from the ventricular zone to the superficial layer in the cerebral cortex. The mRNA expression was detected throughout the postnatal period, and intense signals of the transcript were seen in the ventricle and in layers I, II and III of the cerebral cortex at PD5. Similarly, positive staining of MIF protein was seen in the ventricular zone by immunohistochemical analysis, although the positively stained area appeared to be smaller than the mRNA expression. Taken together, these results suggest that the increase in MIF mRNA in the developing brain reflects the growth and maturation of neurons and glial cells.

Animals↗
PubMed1984

Antagonism of morphine analgesia by prolyl-leucyl-glycinamide (MIF-1) in humans.

Prolyl-leucyl-glycinamide (MIF-1) has been observed to inhibit the analgesic effect of morphine in a series of animal studies. In the present study, the naloxone-like properties of MIF-1 were assessed in human subjects. Eight men received a capsule containing 60 mg of MIF-1 or placebo followed one hour later by a 10 mg intramuscular injection of morphine in a double-blind, crossover design at two visits 4 weeks apart. Experimental pain was induced by the cold pressor test administered 45, 75, 120 and 180 min after the morphine. Each subject recorded severity of pain on a 100 mm line scale every 5 sec during the 120 sec his foot was immersed in the cold water tank and during the 60 seconds immediately following its removal. On a third visit, baseline values were measured in the absence of morphine, MIF-1 or placebo. Analysis of variance revealed that MIF-1 resulted in significantly higher scores (less analgesia) compared with placebo when measured at 45 and 75 min after morphine during the immersion phase and during all four times the subjects were evaluated during the removal phase. The results indicate that MIF-1 can act in humans as an opiate antagonist.

Adult↗
PubMed1999

Inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity by dopachrome analogs.

A macrophage migration inhibitory factor (MIF) dopachrome tautomerization assay was employed for identification of MIF inhibitors. One group of dopachrome analogs was identified which inhibits MIF tautomerase activity. In particular, the analogs with a leaving group at beta position displayed activity at a concentration of tenfold less than that of the MIF-substrate. These findings could lead to a better understanding of MIF biological activities and the development of agents for the treatment of MIF related diseases.

Indolequinones↗
PubMed1993

MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia.

Cytokines are critical in the often fatal cascade of events that cause septic shock. One regulatory system that is likely to be important in controlling inflammatory responses is the neuroendocrine axis. The pituitary, for example, is ideally situated to integrate central and peripheral stimuli, and initiates the increase in systemic glucocorticoids that accompanies host stress responses. To assess further the contribution of the pituitary to systemic inflammatory processes, we examined the secretory profile of cultured pituitary cells and whole pituitaries in vivo after stimulation with bacterial lipopolysaccharide (LPS). Here we identify macrophage migration inhibitory factor (MIF) as a major secreted protein release by anterior pituitary cells in response to LPS stimulation. Serum analysis of control, hypophysectomized and T-cell-deficient (nude) mice suggests that pituitary-derived MIF contributes to circulating MIF present in the post-acute phase of endotoxaemia. Recombinant murine MIF greatly enhances lethality when co-injected with LPS and anti-MIF antibody confers full protection against lethal endotoxaemia. We conclude that MIF plays a central role in the toxic response to endotoxaemia and possibly septic shock.

Acute-Phase Reaction↗
PubMed2003

Macrophage migration inhibitory factor (MIF) gene polymorphism is associated with susceptibility to but not severity of inflammatory polyarthritis.

The aim of the study was to investigate whether polymorphisms of macrophage migration inhibitory factor (MIF) determine susceptibility to or severity of inflammatory polyarthritis (IP). Genotypes for a single-nucleotide polymorphism (MIF-173*G/C) and a tetranucleotide (CATT)(n) repeat mapping to the promoter region of the MIF gene were compared between UK Caucasian IP cases (n=438) and controls (n=343). Both polymorphisms were also investigated for association with features of disease activity and severity at baseline and by 5 years. The MIF-173*C allele (OR 1.7, 95% CI 1.3-2.4, P=1.8 x 10(-4)) and the CATT(7) allele (OR 1.5, 95% CI 1.0-2.1, P=0.02) were found to be associated with increased susceptibility to IP. Furthermore, presence of the haplotype containing both associated polymorphisms was associated with a three-fold increase risk of developing IP. No association with disease severity or activity either at baseline or by 5 years was detected for either of the promoter polymorphisms studied. In conclusion, MIF is a susceptibility gene for the development of IP. The same alleles previously reported to be associated with susceptibility to juvenile idiopathic arthritis account for the increased risk. The promoter polymorphisms of MIF, investigated in this study, do not influence the severity of disease outcome by 5 years.

Adult↗
PubMed1997

Up-regulation of macrophage colony-stimulating factor (M-CSF) and migration inhibitory factor (MIF) expression and monocyte recruitment during lipid-induced glomerular injury in the exogenous hypercholesterolaemic (ExHC) rat.

Although macrophages play an important role in lipid-induced glomerular injury, we know little of the mechanisms by which hyperlipidaemia induces monocyte recruitment. This study investigated the role of M-CSF and macrophage MIF in monocyte recruitment during the development of lipid-induced glomerular injury in the susceptible ExHC rat strain. Groups of five ExHC rats were fed a high cholesterol diet (HCD) containing 3% cholesterol, 0.6% sodium cholate and 15% olive oil, and killed after 3 days, 1, 2 or 6 weeks. Control animals were killed on day 0 or after 6 weeks on a normal diet. Animals were hypercholesterolaemic 3 days after the induction of the HCD, but showed no change in plasma triglycerides over the 6-week period. Glomerular macrophage accumulation was first evident at 1-2 weeks and increased up to week 6, when macrophage-derived foam cells were seen in almost all glomeruli, and segmental lesions and mild proteinuria were also evident. Combined in situ hybridization and immunohistochemistry staining demonstrated that, coincident with the induction of hypercholesterolaemia on day 3, there was marked up-regulation of M-CSF and MIF mRNA expression by intrinsic glomerular cells (mostly mesangial cells and podocytes) which preceded monocyte recruitment. There was a highly significant correlation between the number of M-CSF and MIF-positive cells and glomerular macrophage accumulation over the 6-week period. Although some glomerular macrophages and foam cells exhibited M-CSF and MIF expression, the major source of these molecules was intrinsic glomerular cells. No local macrophage proliferation was observed during the development of glomerular lesions. In conclusion, hypercholesterolaemia caused marked up-regulation of M-CSF and MIF expression by intrinsic glomerular cells, which correlated with monocyte recruitment and the development of lipid-induced glomerular injury. This is the first study to implicate local synthesis of MIF in the pathogenesis of lipid-induced lesions.

Animals↗
PubMed2003

Blockade of macrophage migration inhibitory factor (MIF) in Schistosoma japonicum-infected mice results in an increased adult worm burden and reduced fecundity.

Macrophage migration inhibitory factor (MIF), a cytokine produced by many cell types, modulates cellular and humoral immune responses. In schistosomiasis, ova in the portal circulation induce a delayed type hypersensitivity (DTH) that results in formation of hepatic granulomas (HG) which secrete MIF activity. Therefore, we hypothesized that endogenous MIF modulates immune responses in schistosomiasis. To test this hypothesis, Schistosoma japonicum-infected mice were injected with rabbit IgG or neutralizing rabbit IgG antibody to MIF 4.5-6.5 week post infection when HG form and female worms are laying eggs. Compared with controls, 6.5-7-week post-infection, antibody-treated mice had 1.7-3 times as many adult worms and half as many ova per worm pair in their livers. In contrast, antibody introduced before infection or 6-8 week post infection did not affect worm burden or fecundity. Thus, for the first time there is evidence that 4.5-6 week post-infection endogenous MIF somehow mediates reduction of adult worm burden and promotes fecundity. Splenocytes and HG cells from antibody-treated mice showed reduced intracellular expression of TNFalpha and/or IL-10. We hypothesize that endogenous MIF enhances adult worm attrition by up-regulating innate and adaptive immune responses by increasing expression of MHC-II, co-stimulatory, adhesion, receptor and cytokine molecules, and promotes fecundity by up-regulating TNFalpha expression.

Animals↗
PubMedDate not supplied

Up-regulation and coexpression of MIF and matrix metalloproteinases in human abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) is a localized dilatation of the arterial wall as a result of extensive breakdown of its structural proteins by matrix metalloproteinases (MMPs). AAA continuously expand and may eventually rupture, causing high mortality rates. The molecular processes underlying expansion and rupture of AAA are only poorly understood. In this study, evidence was sought for a direct involvement of macrophage migration inhibitory factor (MIF) in the pathogenesis of AAA through up-regulating MMPs, with particular reference to macrophages. To this end, expression and cellular localization of MIF were analyzed in human aortic wall samples of stable AAA and ruptured AAA, and compared with control aorta and atherosclerotic aorta (AS). MIF expression was up-regulated in stable AAA and further intensified in ruptured AAA. The increased aneurysmal MIF expression was paralleled by an enhanced expression of specific MMPs, viz. MMP-1, MMP-9, and MMP-12, and by a decrease of their inhibitors. Immunohistochemical analysis of AAA and AS showed MIF protein in endothelial cells, smooth muscle cells (SMCs), macrophages, and T cells. MMP-1 (in SMCs and macrophages) and MMP-9 (in macrophages) were colocalized with MIF at the cellular level in ruptured AAA. The up-regulation of aneurysmal MIF/MMP expression was associated with an increased content of cytotoxic T cells.

Aorta↗
PubMed2001

Detection of macrophage migration inhibitory factor (MIF) in human cholesteatomas and functional implications of correlations to recurrence status and to expression of matrix metalloproteinases-3/9, retinoic acid receptor-beta, and anti-apoptotic galectin-3.

OBJECTIVES: To investigate whether the expression of the macrophage migration inhibitory factor (MIF) 1) is detectable, 2) changes in relation to recurrence and infection status, and 3) relates to the levels of expression of growth regulators/differentiation markers, including galectin-1, -3, and -8, retinoid acid receptors (RAR)]-alpha, -beta, and -gamma, binding sites for sarcolectin, and invasion markers (cathepsins -B and -D, and matrix metalloproteinases [MMP]-2, -3, and -9) in human cholesteatomas. STUDY DESIGN: An analysis of 56 cholesteatomas resected by the same surgeon using canal wall up and canal wall down surgical procedures. METHODS: The immunohistochemical levels of expression of MIF and the proteases were quantitatively determined (using computer-assisted microscopy) on routine histologic slides by specific antibodies, and statistically correlated to parameters of the other markers determined previously in conjunction with data on apoptosis/proliferation. RESULTS: MIF expression was detected. It was significantly higher in the epithelium (P =.002) and vessels (P =.04) of the connective tissues (but not in the connective tissue itself) of recurrent as opposed to non-recurrent cholesteatomas. The MIF expression is significantly correlated (P =.006) to the RAR beta expression in non-infected cholesteatomas, and to MMP-3 (P <.01) and anti-apoptotic galectin-3 (P =.01) in infected cholesteatomas. The level of MIF expression was also correlated significantly to MMP-9 (P = 0.003), RAR beta (P <.001), and galectin-8 (P =.003) expression in the cholesteatomas regardless of their infection status. CONCLUSIONS: MIF expression in human cholesteatomas is related to the levels of biologic aggressiveness reflected in their recurrence status and MMP expression, and to the differentiation status reflected in their galactin and RAR beta expressions. Together with galectin-3, it could cooperate to form an anti-apoptotic feedback loop.

Adolescent↗
PubMed1981

The effect of melanotrophin release inhibiting factor (MIF) and cyclo (Leu-Gly) on the tolerance to morphine-induced antinociception in the rat: a dose-response study.

1. The effects of melanotrophin release inhibiting factor (MIF) and its cyclic analogue cyclo (Leu-Gly) on tolerance to the analgesic effect of morphine were studied in male Sprague-Dawley rats. 2. Tolerance to morphine was induced by implantation of four morphine pellets (each containing 75 mg of morphine free base) during a 3 day period. 3. Daily subcutaneous administration of MIF and cyclo (Leu-Gly) before and during the morphine pellet implantation inhibited the development of tolerance to morphine analgesia. The minimum daily dose of the peptides required to produce a significant effect was 0.5 mg/kg. 4. The effects of single injections of MIF and cyclo (Leu-Gly) on morphine tolerance revealed that the minimum doses of cyclo (Leu-Gly) and MIF to inhibit morphine tolerance were 4 and 8 mg/kg, respectively. 5. Chronic treatment with morphine resulted in an enhanced hypothermic response to dopamine agonist, apomorphine. The enhancement of this response was blocked by both MIF and cyclo (Leu-Gly) in doses that inhibited morphine tolerance. 6. It is concluded that MIF and cyclo (Leu-Gly) blocked the development of analgesic tolerance as well as dopamine receptor hypersensitivity induced by chronic morphine treatment and the two phenomena may be interrelated.

Analgesia↗
PubMed1998

Neuroimmunomodulation by macrophage migration inhibitory factor (MIF).

Recent studies have led to the discovery of a mediator that appears to act as an endogenous hormone to counterregulate glucocorticoid action within the immune system. Isolated as a product of anterior pituitary cells, the structure of this protein was found to be that of macrophage migration inhibitory factor (MIF)--one of the first cytokines to be identified and described originally as a T lymphocyte factor that inhibited the random migration of macrophages. Macrophages and T cells release MIF in response to glucocorticoids, as well as upon activation by various proinflammatory stimuli. Once secreted MIF "overrides" the immunosuppressive effects of steroids on macrophage and T-cell cytokine production. MIF appears to fill an important gap in our understanding of how the host initiates and controls the immune response. Because glucocorticoids are an integral part of the host's metabolic "stress" response to infection or tissue invasion, the role of MIF is to act at an inflammatory site or lymph node to counterbalance the inhibitory effects of steroids on the immune response. Anti-MIF therapeutic strategies are under development and may prove to be a means to increase the immunosuppressive and anti-inflammatory properties of endogenously released glucocorticoids, thereby reducing the requirement for steroid therapy in a variety of autoimmune and inflammatory conditions.

Animals↗