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At least 199 records · Page 11Linked to original sources
PubMed1981

Effect of L-prolyl-L-leucyl-glycinamide (MIF-I) on some neutrotransmitter-receptor interactions.

Some neurotransmitter-receptor interactions have been studied in an attempt to determine how L-prolyl-L-leucyl-glycinamide (MIF-I) exerts its antiparkinson effect. MIF-I affected neither the contractile responses of isolated mouse vas deferens and guinea pig ileum to noradrenaline, acetylcholine, substance P and histamine, nor the inhibitory effects of dopamine and GABA on the rat vas deferens and guinea pig ileum. MIF-I, as well as L-leucine and Pro-Leu, antagonized the contractile response of the ileum to 5-hydroxytryptamine (5-HT). Behavioural tests were used to examine the action of MIF-I on CNS transmitter-receptor interactions. MIF-I did not modify the circling produced by either dopamine agonists in nigro-striatal lesioned rats of 5-HT agonists in rats with a lesion of the medial raphe nucleus. MIF-I affected neither 5-hydroxytryptophan-induced head twitches in mice, which is a measure of 5-HT receptor stimulation, nor striatally-evoked head turning in the rat, which is a model for brain GABA function. It is concluded that MIF-I, at the doses used, does not directly modify the function of any of the CNS transmitter examined. Other possibilities to explain its antiparkinson action are discussed.

Acetylcholine↗
PubMed2002

A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis.

The macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine and regulates the anti-inflammator effects of glucocorticoids. An important role for MIF within the cytokine cascade is to act in concert with endogenous glucocorticoids to control the set-point and magnitude of the inflammatory response. Elevated expression of MIF in the circulation and in the synovial joint has been documented in rheumatoid arthritis. MIF also has been linked to the development of joint damage and disease pathology in experimental animal models. We describe herein a novel CATT-tetranucleotide repeat polymorphism at position -794 of the human Mif gene and show that it functionally affects the activity of the MIF promoter in gene reporter assays. We describe four genotypes which comprise 5, 6, 7, or 8-CATT repeat units and show that the 5-CATT allele has the lowest level of basal and stimulated MIF promoter activity in vitro. The presence of the low expressing, 5-CATT repeat allele correlated with low disease severity in a cohort of rheumatoid arthritis patients.

Arthritis, Rheumatoid↗
PubMed2001

Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response.

The importance of the macrophage in innate immunity is underscored by its secretion of an array of powerful immunoregulatory and effector molecules. We report herein that macrophage migration inhibitory factor (MIF), a product of activated macrophages, sustains macrophage survival and function by suppressing activation-induced, p53-dependent apoptosis. Endotoxin administration to MIF(-/-) mice results in decreased macrophage viability, decreased proinflammatory function, and increased apoptosis when compared with wild-type controls. Moreover, inhibition of p53 in endotoxin-treated, MIF-deficient macrophages suppresses enhanced apoptosis and restores proinflammatory function. MIF inhibits p53 activity in macrophages via an autocrine regulatory pathway, resulting in a decrease in cellular p53 accumulation and subsequent function. Inhibition of p53 by MIF coincides with the induction of arachidonic acid metabolism and cyclooxygenase-2 (Cox-2) expression, which is required for MIF regulation of p53. MIF's effect on macrophage viability and survival provides a previously unrecognized mechanism to explain its critical proinflammatory action in conditions such as sepsis, and suggests new approaches for the modulation of innate immune responses.

Animals↗
PubMed2005

ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis.

MIF is a proinflammatory cytokine that has been implicated in the pathogenesis of sepsis, arthritis, and other inflammatory diseases. Antibodies against MIF are effective in experimental models of inflammation, and there is interest in strategies to inhibit its deleterious cytokine activities. Here we identify a mechanism of inhibiting MIF pro-inflammatory activities by targeting MIF tautomerase activity. We designed small molecules to inhibit this tautomerase activity; a lead molecule, "ISO-1 ((S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester)," significantly inhibits the cytokine activity in vitro. Moreover, ISO-1 inhibits tumor necrosis factor release from macrophages isolated from LPStreated wild type mice but has no effect on cytokine release from MIFdeficient macrophages. The therapeutic importance of the MIF inhibition by ISO-1 is demonstrated by the significant protection from sepsis, induced by cecal ligation and puncture in a clinically relevant time frame. These results identify ISO-1 as the first small molecule inhibitor of MIF proinflammatory activities with therapeutic implications and indicate the potential of the MIF active site as a novel target for therapeutic interventions in human sepsis.

Animals↗
PubMed2000

Increased stability of macrophage migration inhibitory factor (MIF) in DU-145 prostate cancer cells.

Macrophage migration inhibitory factor (MIF) has been localized to the glandular epithelium of the prostate and stimulates the in vitro growth of prostate epithelial cells. [35S]Methionine labeling of MIF protein was used to determine if prostate cells synthesize and secrete this cytokine. The results demonstrated that the DU-145 prostate cancer cells secrete about twice the amount of a more stable protein compared with normal prostate epithelial cells. To investigate if differences in MIF mRNA levels account for the differences in MIF protein secreted by these cells, mRNA stability was analyzed by [3H]uridine incorporation. Following a 12-h pulse, DU-145 cells were found to contain four times the amount of [3H]uridine-labeled MIF mRNA, and this message exhibited a longer half-life than the message found in normal cells (33 h and 19 h, respectively). Nuclear run-on experiments confirmed that the MIF gene is transcribed at a greater rate (1.8-fold) in the DU-145 prostate cancer cells. This study documents, for the first time, that human prostate epithelial cells synthesize and secrete this cytokine. These results indicate that the increased levels of MIF found in prostate cancer cells is likely due to the increased protein and mRNA stability as exhibited by DU-145 cells.

Adenocarcinoma↗
PubMed2003

Prognostic values of galectin-3 and the macrophage migration inhibitory factor (MIF) in human colorectal cancers.

This study aims to investigate whether the immunohistochemical levels of expression of galectin-3 and the macrophage migration inhibitory factor (MIF) are associated with prognostic values in human colorectal tumors. This was performed on 99 specimens including 69 colorectal tumors (17 Dukes A, 19 Dukes B, 15 Dukes C and 18 metastatic tumors that we labeled as D), 10 hepatic metastases from colorectal cancers and 20 normal specimens (biopsies). The immunohistochemical levels of expression of MIF and galectin-3 were quantified on routine histological slides by means of computer-assisted microscopy. Separate analyses were performed on epithelial and connective tissue. The levels of expression of both MIF and galectin-3 were very significantly higher in epithelial tumor tissue when compared with normal epithelial specimens. A positive and significant correlation between MIF and galectin-3 expression was evidenced in connective tumor tissue, and in particular in the cases associated with short survival periods (less than 5 years). In the case of the Dukes A or B tumors, we established two new prognostic groups (labeled I and II) on the basis of the levels of galectin-3 expression measured in the tumor epithelium. In the case of the Dukes C or D tumors, we established two other prognostic groups (labeled III and IV) on the basis of the levels of MIF expression measured in the connective tissue. Kaplan-Meyer analyses confirmed the additional prognostic values (as compared with conventional clinical staging) given by this new classification (groups I to IV). They show that the Dukes A or B tumors characterized by low levels of galectin-3 expression in the tumor epithelium are associated with significantly better prognoses than those characterized by high levels. In addition, the Dukes C or D tumors characterized by high levels of MIF expression in the connective tumor tissue are associated with significantly better prognoses than those characterized by low levels. In conclusions, MIF and galectin-3 expression levels in colorectal tumors are related to their levels of biological aggressiveness. These markers could be used to identify patients at risk, for whom more aggressive adjuvant therapy seems to be indicated.

Adenocarcinoma↗
PubMed1979

Partial purification of guinea pig MIF by affinity column chromatography using macrophages.

First we have confirmed the previous observation that the macrophage migration inhibitory factor (MIF) was adsorbed on normal peritoneal macrophages when they were incubated at 4 C for 60 min. It was found that macrophages fixed with 2% glutaraldehyde gave more reproducible results than viable cells in terms of "adsorption" of guinea pig MIF. The adsorption was achieved more completely at 37 C than at 4 C, indicating that this reaction is a temperature-dependent phenomenon. Using these glutaraldehyde-fixed macrophages, a kind of cell-affinity column was successfully developed. The guinea pig MIF preparation lost its activity when it was passed through this affinity column, and MIF adsorbed on the column was recovered by elution with 0.1 M (L)-fucose of 0.1 M (D)-glucose. Such MIF active eluate was found to be at least 30--40 fold more pure than the original MIF preparation which had been previously fractionated according to its molecular weight. Therefore, this type of macrophage-affinity column may be useful for the purification of MIF.

Adsorption↗
PubMed2003

Macrophage migration inhibitory factor (MIF): Its potential role in tumor growth and tumor-associated angiogenesis.

Macrophage migration inhibitory factor (MIF) functions as a pluripotent cytokine involved in broad-spectrum pathophysiological events in association with inflammation and immune responses. Several reports, including ours, have suggested that MIF is also involved in tumorigenesis; however, its precise role has not been fully investigated. We examined the effectiveness of anti-MIF antibodies on tumor growth and tumor-associated angiogenesis using murine colon cancer cell line, colon 26. We observed a significant inhibition of growth of tumors embedded on the back of BALB/c mice by treatment with anti-MIF antibodies. Next, we implanted a Millipore chamber filled with colon cancer cells in the subcutaneous fascia of the flanks of mice and then treated them with anti-MIF antibodies. We found that angiogenesis was markedly suppressed within the region of the subcutaneous fascia that was in contact with the chamber. To further assess the role of MIF in tumorigenesis, we established MIF transgenic mice, which demonstrated that tumor growth and the associated angiogenesis were significantly enhanced in comparison with control mice.

Animals↗
PubMed1987

Hypophysectomy increases TYR-MIF-1-like immunoreactivity in rat plasma.

Complex interactions of the pituitary, hypothalamus, and pineal involving MIF-1 (Pro-Leu-Gly-NH2) were shown many years ago. One of the largest changes consisted of increased amounts of an MIF-1-like material in the plasma of hypophysectomized rats as measured by the skin lightening of darkened frogs. The present study used radioimmunoassay to measure immunoreactive Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) in intact, hypophysectomized, pinealectomized, and superior cervical ganglionectomized (SCG) rats. Samples were collected every 4 h for 24 h. Plasma concentrations of Tyr-MIF-1-like immunoreactivity were higher in hypophysectomized rats and lower in pinealectomized rats than in the intact or SCG groups, which were not reliably different from each other. In most groups, the highest plasma concentrations appeared to occur about 04.00 h, a time at which brain concentrations of Tyr-MIF-1-like immunoreactivity were low. However, no diurnal rhythm in plasma was seen in the pinealectomized rats. At none of the times did brain concentrations of immunoreactive peptide differ among the four groups. By high-performance liquid chromatography of plasma, the main peak of immunoreactivity was found to elute at the same position as Tyr-MIF-1, supporting the natural occurrence of this tetrapeptide. Thus, this study demonstrates that the concentration of immunoreactive Tyr-MIF-1 in plasma is increased by hypophysectomy.

Animals↗
PubMed1995

Cloning and characterization of the gene for mouse macrophage migration inhibitory factor (MIF).

An emerging body of data indicates that the protein mediator described originally as macrophage migration inhibitory factor (MIF) exerts a central and wide ranging role in host inflammatory responses. MIF is a major constituent of corticotrophic cells within the anterior pituitary gland and is secreted into the circulation in a hormone-like fashion. MIF also exists performed in monocytes/macrophages and is a pivotal mediator in the host response to endotoxic shock. To gain further insight into the biologic expression of this protein that encompasses components of both the immune and the endocrine systems, we have cloned the mouse MIF gene and identified potential regulatory sequences present within the 5'-proximal promoter region. The gene for mouse MIF is located on chromosome 10, spans approximately 1 kb, and shares a high degree of structural homology with its human counterpart. Of note, the consensus enhancer/promoter motifs identified include both inflammatory/growth factor-related elements and sites associated with the genes for certain peptide hormones. We also report the structures of two MIF pseudogenes that account for early observations suggesting that mouse MIF is encoded by a highly homologous multigene family.

Amino Acid Sequence↗
PubMed1984

Looking for relationships between the most repeated dispersed DNA sequences in the mouse: small R elements are found associated consistently with long MIF repeats.

Four highly-repeated dispersed DNA sequence families have been described in the mouse genome. These are the three small elements B1, B2 and R and the large (6 kb) MIF element. Together these comprise approximately 10% of the mouse genome. Possible relationships between these families are pertinent to the genome as a whole. We report here that the B1s, B2s and Rs are all randomly organized in the genome with respect to each other. Surprisingly though, the R and MIF families are found together consistently in a set of random genomic clones and in selected clones. We find Rs often located on one end of the MIF at a consistent site and conclude that a minority of Rs are an integral part of MIF while the majority of Rs are not associated with MIFs. We propose that isolated R elements are truncated forms of MIF. Also we speculate on the mechanism of dispersal of these elements through the mouse genome.

Animals↗
PubMed1995

Evidence that MIF plays a role in the development of pigmentation patterns in the frog.

A ventrally localized melanization-inhibiting factor (MIF) may play an important role in the expression of dorsal-ventral pigment patterns of amphibians. In efforts to purify this putative MIF, ventral skin conditioned medium (VCM) from Rana forreri was partially fractionated and used to immunize mice. A monoclonal antibody that has the ability to block the activity of MIF was isolated, and an immunoaffinity matrix was prepared by cross-linking the antibody to protein G-Sepharose. The fraction of VCM that bound to the affinity matrix decreased the number of melanized cells in the Xenopus laevis neural tube explant assay, but did not reduce significantly the number of cells that emigrated. The monoclonal antibody was used for immunohistochemical studies on R. pipiens skin. Strong staining with the antibody was observed beneath the basement membrane, in mucous glands, and in the subcutaneous tissue of the ventral skin. A weak staining was also observed in the ground substances of both ventral and dorsal skin. These results confirm that a monoclonal antibody has been secured against at least one of the MIF constituents and that it is useful as a probe in detecting the distribution of MIF in tissues. The results of its use in this study support the hypothesis that MIF plays a role in the expression, development, and maintenance of the dorsal-ventral pigmentation patterns of frogs.

Animals↗
PubMed2002

Human cytomegalovirus-mediated induction of MIF in fibroblasts.

Human cytomegalovirus (HCMV) infection of fibroblasts induces the proinflammatory mediator macrophage migration inhibitory factor (MIF). Our in vitro experiments show that active HCMV infection alone is required to induce an early and sustained induction of MIF mRNA and protein production. Unlike in other infection models, in which MIF has been described to be released from preformed stores, our data conclusively show that HCMV infection triggers de novo synthesis and subsequent secretion of MIF. The kinetics of MIF protein production during HCMV infection points to an efficacious immune modulation, in which lymphocytes and monocytes are initially recruited by the early release of chemokines to sites of infection and locally activated by increasing concentrations of MIF.

Blotting, Northern↗
PubMed1989

MIF-1 attenuates apomorphine stereotypies in adult rats after neonatal 6-hydroxydopamine.

Since prolyl-leucyl-glycinamide (MIF-1) modifies the behavior of adult rats after treatment with neuroleptics, we examined whether MIF-1 would also modify adult behavior after treatment of neonatal rats with 6-hydroxydopamine (6-OHDA). Rats received 6-OHDA (100 micrograms i.c.v.) or diluent at 3 days after birth and either MIF-1 (2.0 mg/kg per day s.c. x 10 days) or diluent beginning at 28 or 29 days after birth. At 5 weeks, a low dose (0.1 mg/kg s.c.) of apomorphine increased the distance traveled, time in ambulation, number of stereotypic movements, and number of movements per time in stereotypy, but decreased the time in stereotypy in the 6-OHDA group. MIF-1 (x 7 or 8 days) showed a tendency to attenuate the increased number of movements and significantly (P less than 0.05) reduced all of the other effects of neonatal 6-OHDA. Behavior induced by higher doses of apomorphine in the 6-OHDA group (reduced licking and head nodding; increased paw treading, taffy pulling and self-biting) were not attenuated by MIF-1. At 38 or 39 days, total in vitro binding of [3H]SCH-23390 and [3H]spiroperidol to striatal homogenates was not altered in any of the groups. The findings demonstrate that specific early developmental alterations in apomorphine-induced behaviors can be modified by treatment of adult rats with MIF-1, even in the absence of overt changes in the binding of striatal dopamine D-1 and D-2 receptors.

Animals↗
PubMed1976

Effects of L-prolyl-L-leucyl-glycine amide (MIF-I) on dopaminergic neurons.

In an attempt to determine the mechanism of action of L-proly-L-leucyl-glycine amide (MIF-I) in the treatment of Parkinson's disease, various parameters of dopaminergic neuronal function were studied in rats. It was found that the active uptake of 3H-dopamine (3H-DA) by synaptosome-rich homogenates of the striatum of rats treated with MIF-I (1 mg/kg IP X 3, 24 hr intervals) was unaltered 1 hr after final treatment with MIF-I. Also, neither tyrosine hydroxylase nor dopa decarboxylase activity was altered in the striatum and substantia nigra of rats treated with MIF-I (20 mg/kg IP X 3, 24 hr intervals). Thus, vital functional processes associated with dopaminergic neurons apparently are not altered by MIF-I under the conditions studied. These findings illustrate the importance of concurrent DOPA administration in observing an effect of MIF-I on dopaminergic neuronal function.

Animals↗
PubMed1980

Naloxone-like actions of MIF-1 do not require the presence of the pituitary.

The actions of peripherally administered MIF-1 (Pro-Leu-Gly-NH2) and naloxone in blocking the effects of morphine in the tail-flick test were measured across a wide range of five doses in hypophysectomized and intact mice. The presence of the pituitary gland failed to influence the response to MIF-1 or naloxone. Both hypophysectomized and intact mice were significantly affected by these two compounds at doses of 0.01, 0.1, 1.0, and 10.0 mg/kg IP. The greatest effect of MIF-1 occurred at 100 mg/kg, but naloxone was lethal at this dose. Preliminary experiments with other tests showed that at 10 mg/kg, naloxone, but not MIF-1, was effective in preventing the Straub-tail reflex and in precipitating withdrawal-jumping in mice implanted with morphine pellets. Only minimal activity was shown by MIF-1 in preventing blockade of electrically induced contractions of the guinea pig ileum by morphine. Neither compound was active in the frog-righting test. In summary, the results emphasize the differential actions of MIF-1 as an opiate antagonist and demonstrate that the pituitary is not required for their mediation.

Animals↗
PubMed1982

MIF-1 does not act like naloxone in antagonizing the cardiovascular activity of leucine-enkephalin in the conscious dog.

MIF-1 (Pro-Leu-Gly-NH2), a hypothalamic tripeptide, has been demonstrated to stimulate naloxone in antagonizing the effects of opioid peptides in a number of experimental systems including enkephalin-induced analgesia in the tail-flick assay, beta-endorphin induced hypothermia and hypomotility, deprivation-induced drinking, and analgesia in goldfish. MIF-1, however, has no effect upon the activity of enkephalins in the mouse vas deferens or enkephalin binding in the rat striatum. We have studied the interactions of MIF-1 with Leu5-enkephalin (Leu5-ENK) in the conscious, chronically instrumented dog. Although naloxone inhibits both the elevations of heart rate and blood pressure produced by IV Leu5-ENK in the conscious state and the depressions in these variables produced by Leu5-ENK after pentobarbital anesthesia, MIF-1 has no effect upon the Leu5-ENK response in either state. However, both naloxone and MIF-1 seem to raise mean arterial pressure in the conscious dog. These results indicate that MIF-1 does not act like naloxone in antagonizing the peripheral effects of Leu5-ENK and lend further support to the existence of mechanistic differences among opiate-mediated behavior, analgesia, and cardiovascular activity.

Animals↗
PubMed1982

MIF-1: effects on norepinephrine, dopamine and serotonin metabolism in certain discrete brain regions.

A single injection of melanocyte-stimulating hormone inhibitory factor (MIF-1) in a dose of 3 mg/kg IP produced no significant effect on dopamine turnover. However, a dose of 5 mg/kg increased striatal tyrosine hydroxylase activity by 25% and homovanillic acid level by 27% when compared to control values. No change in either parameter was detected in olfactory tubercles. Dopamine levels also were elevated in striatum, pons-medulla and cerebral cortex in rats receiving 5 mg/kg dose of MIF-1. In olfactory tubercles, dopamine levels were however, reduced to 71% of control values taken as 100%. The concentration of norepinephrine tended to increase in several brain areas examined but, the change was statistically significant only in olfactory tubercles and cerebral cortex. The level of norepinephrine metabolite, 3-methoxy-4-hydroxyphenylethylene glycol, was lowered to 63% in whole brain of animals given MIF-1 at the dose of 5 mg/kg. These data suggest that MIF-1 enhances the turnover of dopamine and norepinephrine in the brain. However, MIF-1 treatment seemed to produce no consistent change in brain serotonin turnover. In striatum and cortex, this neuropeptide increased serotonin but elevated the level of its metabolite, 5-hydroxyindoleacetic acid indicating that the release of this brain amine was decreased in these two brain regions. The levels of 5-hydroxyindoleacetic acid were enhanced in hypothalamus and pons-medulla regardless of the dose of MIF-1 administered.

Animals↗