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PubMed1991

Dopamine receptor antagonists block the effect of Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) on the opiate form of footshock-induced analgesia.

Previous studies have shown that some of CNS actions of an endogenous peptide Tyr-MIF-1, are mediated by dopamine (DA) receptors. To study the effect of DA receptor blockade on the antiopiate properties of Tyr-MIF-1, the opiate form of footshock-induced analgesia was elicited in the rat. The nociceptive responses were determined using the hot-plate test (52.5 degrees C). Intraperitoneal pre-treatment with haloperidol (500 micrograms/kg), SCH 23390 (150 micrograms/kg), or spiroperidol (150 micrograms/kg) potentiated the antinociceptive effect of the footshock and blocked the antagonistic action of Tyr-MIF-1 (200 micrograms/kg and 2.0 mg/kg). A dose of haloperidol too small to potentiate the antinociceptive effect of the footshock (100 micrograms/kg) was still able to block the action of Tyr-MIF-1 (200 micrograms/kg). The results suggest that activation of DA receptors mediates the antagonizing effect of Tyr-MIF-1 on the opiate form of footshock-induced analgesia in the rat.

Amino Acid Sequence↗
PubMed1995

Increase in plasma TYR-MIF-1-like immunoreactivity after hypophysectomy is robust and reversible by corticosterone.

Tyr-MIF-1-like immunoreactivity (Tyr-MIF-1-LI) was measured in the plasma of hypophysectomized rats. The concentrations were increased in every rat examined, regardless of sex or time after hypophysectomy, and ranged from 2.5 to 10 times greater than the concentrations in intact rats. The elevated concentrations were not decreased by replacement by thyroxine, estrogen and progesterone, or acute injection of corticosterone. Chronic administration of physiological doses of corticosterone, however, did reduce the concentrations to normal. High performance liquid chromatography of tritiated Tyr-MIF-1 incubated at 37 degrees C for 3 min in plasma obtained by hypophysectomized rats eliminated the possibility that reduced degradation of Tyr-MIF-1 explained the increased concentrations. Thus, the increase in Tyr-MIF-1-LI in the plasma of hypophysectomized rats is robust and reversible by chronic replacement of corticosterone.

Animals↗
PubMed1994

The Tyr-MIF-1 family of peptides.

A review of research on the Tyr-MIF-1 family of peptides is presented with emphasis on Tyr-MIF-1 and its structure, passage through the blood-brain barrier, and both opiate antagonist and agonist properties. Family members MIF-1, Tyr-W-MIF-1 and Tyr-K-MIF-1 are also included.

Animals↗
PubMed1980

Lack of suppression of lymphocyte MIF production by estradiol, progesterone and human chorionic gonadotropin.

The hypothesis that hormones produced by the placenta contribute to immunosuppression during pregnancy is an attractive one. In order partially to evaluate this hypothesis, we utilized the Migration Inhibition Factor (MIF) Assay, which is an in vitro model of delayed hypersensitivity in that presensitized lymphocytes stimulated by antigen release a glycoprotein (MIF) which inhibits the normal migration of macrophages. The effect of placental hormones on this model of cellular immunity was tested using the direct and indirect MIF assays in pre-immunized guinea pigs. Estradiol (1-50 microgram/ml), progesterone (1-50 microgram/ml) and commercial grade or chromatography-purified hCG (1000-5000 IU/ml) did not affect normal macrophage migration and also failed to suppress production of MIF by guinea pig lymphocytes stimulated with antigen. None of the hormones either enhanced or suppressed macrophage response to preformed MIF. The results indicate that these hormones do not suppress lymphocyte reactivity as assessed by the production of lymphokines or the target cell response to the mediator. The reported effects of steroid hormones and crude hCG on other models of cellular immunity are discussed.

Animals↗
PubMedDate not supplied

MIF-1 potentiates the action of tricyclic antidepressants in an animal model of depression.

In the present paper, the effect of simultaneous treatment of rats with low doses of MIF-1 and tricyclic antidepressants on rat behavior in the forced swim test was studied. It was found that MIF-1 stimulated in a dose-dependent manner "active" behavior of animals in this paradigm. The effect of MIF-1 appeared to be independent of changes in rats' locomotion in the open field test. The combined treatment of rats with MIF-1 (0.01 mg/kg IP) and amitriptyline (5 mg/kg IP) or desipramine (1.25 mg/kg) IP) significantly stimulated active behavior in the forced swim test above the level obtained with each of the drugs given separately. The present data suggest the potential clinical efficacy of a combined therapy of depressive patients with MIF-1 and small doses of tricyclic antidepressants.

Amitriptyline↗
PubMedDate not supplied

Sex differences in the effects of Tyr-MIF-1 on morphine- and stress-induced analgesia.

There is evidence suggesting that the endogenous tetrapeptide, Tyr-MIF-1 (Tyr-Prol-Leu-Gly-amide), has antagonistic or modulatory effects on opioid-mediated analgesia. There is also substantial evidence for sex differences in opioid effects, whereby male rodents display greater levels of opioid-mediated analgesia than females. In the present study, determinations were made of the effects of Tyr-MIF-1 on morphine- and restraint stress-induced opioid analgesia in adult male and female deer mice, Peromyscus maniculatus. Intraperitoneal treatment with Tyr-MIF-1 (0.10-10 mg/kg) reduced morphine- and stress-induced analgesia in both male and female mice, with Tyr-MIF-1 having markedly greater antagonistic effects in male than female mice. These results indicate that there are sex differences in the modulatory (antiopiate) effects of Tyr-MIF-1 on opioid-mediated analgesia.

Amino Acid Sequence↗
PubMedDate not supplied

Oral administration of Tyr-MIF-1 stimulates gastric emptying and gastrointestinal motility in rodents.

The effects of orally administered Tyr-MIF-1, an agonist of an endogenous antiopiate system, were examined on gastric emptying in mice and gastrointestinal myoelectric activity in rats. Tyr-MIF-1 (5 mg/kg in mice, 20 mg/kg in rats) accelerated gastric emptying of a methylcellulose test meal, increased the frequency of antral spike bursts, and disrupted intestinal migrating myoelectric complexes. These effects were reproduced by a subcutaneous administration of Tyr-MIF-1 at the same dosage. They were blocked by naloxone (1 mg/kg) but not by the kappa receptor subtype antagonist MR 2266 (1 mg/kg). The GABAA antagonist bicuculline (0.5 mg/kg), but not the GABAB antagonist 2-hydroxysaclofen (4 mg/kg), also antagonized the effects of Tyr-MIF-1. These data demonstrate that oral Tyr-MIF-1 stimulates gastric emptying and gastrointestinal motility through a systemic or central action that involves opioid and GABA systems.

Administration, Cutaneous↗
PubMedDate not supplied

MIF-I and postsynaptic receptor sites for dopamine.

In an attempt to determine the mechanism by which the tripeptide l-prolyl-l-leucyl-glycine amide (PLG, MIF-I) exerts its antiparkinsonian effect, the action of this substance on various postsynaptic components of striatal dopaminergic nerves was studied. It was shown that injection of rats with MIF-I (1 mg/kg, IPX5, 24 hr intervals) did not alter tyrosine hydroxylase, dopa decarboxylase, choline acetyltransferase and glutamic acid decarboxylase activities in the striatum under the conditions tested. The activities of adenylate cyclase, dopamine-stimulated adenylate cyclase, and guanylate cyclase were not altered in vitro by various concentrations of MIF-I (0.1 to 1000 micrometer), although VIP and neurotensin had some effect. Also the rate of uptake of 3H-dopamine by rat striatal synaptosomes was unchanged, as was the binding of 3H-dopamine and 3H-spiperone to beef caudate membranes. This series of studies indicates that MIF-I does not act directly on the striatal dopamine postsynaptic receptor under the conditions tested, although it is possible that MIF-I could act indirectly at this or another site in vivo by releasing or activating some other factor.

Adenylyl Cyclases↗
PubMed1989

Differential effects of Tyr-MIF-1 and naloxone in two animal models involving benzodiazepine.

It has been shown previously that the endogenous brain peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) can act as an antiopiate and can also increase binding and function at the GABAA/benzodiazepine receptor complex. We now describe the effects of this tetrapeptide in two models in which the antiopiate naloxone has been reported to decrease the activity of benzodiazepines. Unlike naloxone, Tyr-MIF-1 and MIF-1 neither prevented chlordiazepoxide-induced locomotor hyperactivity in mice on a tilting floor nor suppressed chlordiazepoxide-induced eating in rats. Thus, in these two systems, Try-MIF-1 did not act as an antiopiate or alter the effects of a benzodiazepine, indicating a selectivity in the actions of Tyr-MIF-1.

Animals↗
PubMed1996

MIF re-discovered: pituitary hormone and glucocorticoid-induced regulator of cytokine production.

The protein mediator known as macrophage migration inhibitory factor (MIF) was one of the first cytokine activities to be discovered and was described 30 years ago to be a T cell-derived factor that inhibited the random migration of macrophages. Despite the long-standing association of MIF with activated lymphocytes, the precise role of MIF in host responses remained undefined. Recent studies however, have led to the description of a pituitary mediator that appears to act as the natural, counter-regulatory hormone for glucocorticoid action within the immune system. Isolated as a product of an anterior pituitary cell line, this protein was sequenced and found to have the same structure as MIF. The major role of MIF appears to be to act at an inflammatory site or lymph node to counter-balance the inhibitory effects of steroids on the primary immune response, which must necessarily be mounted to eliminate the source of infection or tissue invasion.

Animals↗
PubMed2005

Is macrophage migration inhibitory factor (MIF) the "control point" of vascular hypo-responsiveness in septic shock?

Macrophage migration inhibitory factor (MIF), a member of the cytokine family, is beginning to be recognized as a pleiotropic proinflammatory molecule. MIF exerts function via antagonistic regulation of glucocorticoids, inhibition to apoptosis-mediated p53, influence on vasodilator gas NO and inducible nitric oxide synthase (iNOS), feedback counter-regulation of complement C5a controlling MIF release, and interaction with major cations as well. Interestingly, aforementioned glucocorticoids, apoptosis, NO, iNOS, C5a, Ca2+, Mg2+, Na+, K+, and H+ that are greatly associated with vascular tone or vasomotion. Nevertheless, the elevated serum and cytosolic concentrations of MIF exactly affect all above facets in septic shock models and patients, during which vasodilation of the peripheral resistance vessels occurs, and accompanied with decreased responsiveness to vascular pressors. Thus MIF may bring into play as one of point-controlling proteins in the onset of sustained vascular hypo-reactivity during the process of septic shock.

Animals↗
PubMed2005

Macrophage migration inhibitory factor MIF interferes with the Rb-E2F pathway.

Macrophage migration inhibitory factor (MIF) is implicated in the regulation of inflammation and cell growth. We previously showed that MIF is a potent modulator of p53- and E2F-dependent pathways that are activated in response to oncogenic signaling. Here, we characterize the functional link between MIF and E2F transcription factors. Our results demonstrate that MIF-deficient cells exhibit E2F-dependent growth alterations and reduced susceptibility to oncogenic transformation. The basis for this transformation resistance is a perturbed function of the C-terminal Rb binding region of E2F4. However, inactivation of Rb or substitution of the E2F4 C-terminal domain by the E2F1 C-terminal region rescues the transformation defect. Importantly, the involvement of E2F factors in DNA replication rather than in regulation of transcription determines their oncogenic properties in the context of MIF deficiency. A proinflammatory molecule interfering with tumor suppression and DNA replication provides a compelling molecular link for the association of chronic inflammation and tumorigenesis.

Animals↗
PubMed1986

Generation and characterization of a monoclonal antibody (1C5) to human migration inhibitory factor (MIF).

A monoclonal antibody was raised in mice against human MIF of the Mr 14,000 kd, produced by Concanavalin A-stimulated peripheral blood mononuclear cells. A hybridoma (1C5) secreting an IgG 1 antibody was selected which binds, yet does not neutralize MIF in the macrophage migration assay. MIF activity may be released from immobilized antibodies by acidic buffer elution. The eluate consists of three major bands at Mr 8,000, 14,000 and 28,000 as revealed by SDS-polyacrylamide gel electrophoresis and molecular sieve chromatography (HPLC). By radioimmunoassay and enzyme-linked immunoassay, it could be shown that the antibody binds material with isoelectric points of 4.5 to 5.0 and of 3.0, which coincides precisely with the biological activities. Similar congruencies between the distribution of biologically reactive and binding material were found in molecular sieve and ion exchange chromatography. It is concluded that the antibody 1C5 reacts with most molecular weight entities of MIF which seem to be structurally related and which display similar characteristics as described for guinea pig and mouse MIF.

Antibodies, Monoclonal↗
PubMedDate not supplied

MIF regulates innate immune responses through modulation of Toll-like receptor 4.

Macrophages are pivotal effector cells of the innate immune system, which is vital for recognizing and eliminating invasive microbial pathogens. When microbial products bind to pathogen-recognition receptors, macrophages become activated and release a broad array of cytokines that orchestrate the host innate and adaptive immune responses. Initially identified as a T-cell cytokine, macrophage migration inhibitory factor (MIF) is also a macrophage cytokine and an important mediator of inflammation and sepsis. Here we report that MIF is an essential regulator of macrophage responses to endotoxin (lipopolysaccharide) and Gram-negative bacteria. Compared with wild-type cells, MIF-deficient macrophages are hyporesponsive to lipopolysaccharide and Gram-negative bacteria, as shown by a profound reduction in the activity of NF-kappaB and the production of tumour-necrosis factor-alpha. This reduction is due to a downregulation of Toll-like receptor 4 (TLR4), the signal-transducing molecule of the lipopolysaccharide receptor complex, and is associated with decreased activity of transcription factor PU.1, which is required for optimal expression of the Tlr4 gene in myeloid cells. These findings identify an important role for MIF in innate immunity and provide a molecular basis for the resistance of MIF-deficient mice to endotoxic shock.

Animals↗
PubMed1986

Lymphokine (MIF) production by glomerular T-lymphocytes in experimental glomerulonephritis.

Glomerular T-lymphocyte infiltration has recently been demonstrated to precede glomerular macrophage influx in a pre-immunized model of anti-glomerular basement-membrane antibody-induced glomerulonephritis (antiGBM-GN). In the current study, the functional role of these glomerular T-lymphocytes in directing macrophage localization was sought by measuring their production of macrophage migration inhibition factor (MIF). MIF activity in supernatants from cultured isolated glomeruli was measured in a conventional capillary tube bioassay. Glomerular T-lymphocytes (OX19 positive cells) were maximal (1.95 +/- 0.19 cells/glomerular cross section, c/gcs) 24 hours after injection of antiGBM antibody into sensitized animals. Seventy-two hours after antibody injection, T-lymphocyte numbers were reduced (1.02 +/- 0.14 c/gcs) while macrophage accumulation was maximal (at 24 hrs 4.2 +/- 1.3 macrophages/glomerulus (m/g), at 72 hrs 19.8 +/- 3.7 m/g). MIF activity was only detected in supernatants from T-lymphocyte infiltrated glomeruli (12 hrs 40.81 +/- 4.32% migration inhibition, 24 hrs 45.11 +/- 4.11% migration inhibition, 48 hrs 38.24 +/- 3.53% migration inhibition, 72 hrs 20.86 +/- 3.85% migration inhibition, all P less than 0.05). Control glomeruli from normal animals, pre-immunized animals given normal sheep globulin, pre-immunized animals given anti-GBM antibody and Cyclosporin A, and non-pre-immunized animals given antiGBM antibody did not contain glomerular T-lymphocytes, and their supernatants contained no MIF activity. This data indicates that the glomerular T-lymphocytes in pre-immunized antiGBM-GN are sensitized cells which release MIF and thus may direct glomerular macrophage localization in this model of antibody-induced glomerulonephritis.

Animals↗
PubMed2006

MIF: a new cytokine link between rheumatoid arthritis and atherosclerosis.

Macrophage migration inhibitory factor (MIF) is well established as a key cytokine in immuno-inflammatory diseases such as rheumatoid arthritis. Inflammation is now also recognized as having a crucial role in atherosclerosis, and recent evidence indicates that MIF could also be important in this disease. Here, we review the role of MIF in rheumatoid arthritis and atherosclerosis, discuss the ways in which MIF and its relationship with glucocorticoids could link these diseases, and consider the potential of MIF as a new therapeutic target for small-molecule and antibody-based anti-cytokine drugs.

Animals↗
PubMed1998

Diarrhoeal enterotoxin production by psychrotrophic Baccillus cereus present in reconstituted milk-based infant formulae (MIF).

One hundred reconstituted milk-based infant formulae (MIF) representative of 10 leading brands available in many European Economic Community countries were examined for psychrotrophic Bacillus cereus and for the presence of diarrhoeal enterotoxin. Of the 38 B. cereus isolates recovered from MIF, one, four and 16 strains grew at 4, 6 and 8 degrees C after 15 d. One (2.6%), two (5.3%) and six (15.8%) of the isolates were identified as potential psychrotrophic food poisoning strains as they were both enterotoxigenic and exhibited good growth at 4, 6 and 8 degrees C, respectively. Enterotoxin was not detected in MIF in which less than 5.36 log10 cfu of B. cereus ml-1 had grown. While psychrotrophic enterotoxigenic B. cereus strains occur occasionally in MIF, brief storage of reconstituted MIF at the recommended refrigeration temperature of 4 degrees C will allow this product to remain safe for consumption.

Animals↗