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A lymphokine resembling transfer factor that stimulates MIF production by nonsensitive lymphocytes.

High potency preparations of a new heat-labile, low m.w. (less than 5000) lymphokine (LMWL) were obtained by culturing tuberculin-sensitive guinea pig peritoneal exudate cells (PEC) with PPD in geometric conditions that promote amplified lymphokine production. This LMWL has the ability, in the presence of PPD, to stimulate nonsensitive PEC to produce a heat-stable molecule(s) resembling MIF with a m.w. in the range 50,000 to 100,000. The effects of the LMWL (less than 5000 daltons) and the MIF-like molecule(s) (50,000 to 100,000 daltons) were defined by the indirect macrophage migration assay and a macrophage deoxyglucose uptake assay. It is possible that LMWL represents a form of transfer factor with the ability to recruit unsensitized lymphocytes to produce MIF.

Animals↗

MIF Promoter Variant rs755622 (-173G/C) in Younger and Older Turkish Adults: An Exploratory Cross-Sectional Genetic and in Silico Analysis.

Age-associated immune-inflammatory remodeling may be influenced by regulatory variation in the macrophage migration inhibitory factor gene (MIF). We conducted an exploratory cross-sectional comparison to assess whether MIF rs755622 (-173G/C) genotype distributions differ between predefined younger and older age groups in a Turkish population and to characterize the observed pattern using genetic-model and in silico analyses. We evaluated 368 individuals: 245 older adults aged 65-102 years and 123 younger controls aged 20-46 years. None of the 26 main association tests remained statistically significant after global multiplicity correction (minimum FDR q = 0.062; minimum Bonferroni-adjusted p = 0.108). Before correction, GC frequency was higher in the older group and increased across the ordered age categories, and sex-adjusted analyses yielded concordant nominal estimates. However, these nominal patterns were sensitive to younger-control genotype reclassification and were not supported by an allele-level or additive association. Younger controls showed Hardy-Weinberg disequilibrium (p < 0.001), without sequencing confirmation, and deterministic and scenario-based Monte Carlo genotype-reclassification analyses indicated sensitivity of the nominal signal to uncertainty in control genotype classification. GTEx data provide C-allele-oriented expression context but do not validate function in this cohort. These preliminary findings warrant independent genotype verification, ancestry-matched replication, and direct functional investigation in future studies.

Humans↗

Mouse bone marrow-cultured macrophage as indicator cells for mouse and human migration inhibitory factor (MIF).

Macrophages cultured from mouse bone marrow served as excellent indicator cells for mouse as well as for human migration inhibitory factor (MIF) preparations. The tests were performed in the capillary system and showed high reproducibility. Using mouse or human MIF-containing supernatants, we found an inhibition of 53% compared with the controls. Similar results were obtained if concanavalin A-stimulated human peripheral blood lymphocytes were mixed with mouse test macrophages in a ratio of 1:5 or 1:10.

Animals↗

Genomic cloning of mouse MIF (macrophage inhibitory factor) and genetic mapping of the human and mouse expressed gene and nine mouse pseudogenes.

The single functional mouse gene for MIF (macrophage migration inhibitory factor) has been cloned from a P1 library, and its exon/intron structure determined and shown to resemble that of the human gene. The gene was mapped to chromosome 10 using two multilocus crosses between laboratory strains and either Mus musculus musculus or Mus spretus. Nine additional loci containing related sequences, apparently all processed pseudogenes, were also mapped to chromosomes 1, 2, 3, 7, 8, 9, 12, 17, and 19. While most of these pseudogenes were found in inbred mice and M. spretus, some are species specific. This suggests that there have been active phases of pseudogene formation in Mus both before and after the separation of musculus and spretus. The human genome contains no pseudogenes; we assigned the human gene to chromosome 19, consistent with the location of mouse and human functional genes for MIF in a region of conserved linkage.

Amino Acid Sequence↗

Failure of MIF-I to affect behavioral responses in patients with Parkinson's diseases under L-dopa therapy.

In eight subjects with Parkinson's disease under an optimal daily dose of L-dopa, acute administration of MIF-I (200 mg i.v.) did not ameliorate either the total disability score or the intellectual test PM 38 when evaluated in comparison with the effect induced by acute administration of a placebo. Also concomitant evaluation of the effect of MIF-I on the secretion of anterior pituitary hormones which are under dopaminergic control i.e., growth hormone and prolactin, did not reveal any potentiation of the L-dopa-induced stimulus.

Aged↗

Effect of neurotransmitters on the system that transports Tyr-MIF-1 and the enkephalins across the blood-brain barrier: a dominant role for serotonin.

Neurotransmitters and neuropeptides interact in several ways. We studied a new type of interaction: the effect of neurotransmitters on the saturable system that transports Tyr-MIF-1 and the enkephalins out of the central nervous system (CNS). The neurotransmitters were introduced into the lateral ventricle of the brain with radioiodinated peptide, using an established method previously shown to accurately quantify the amount of peptide being transported from the CNS to the blood. Serotonin inhibited transport, histamine stimulated transport, and dopamine, acetylcholine, epinephrine, GABA, kainic acid, cAMP and cGMP were without effect. Cyproheptadine, a serotonin antagonist, stimulated transport. Of several psychotropic agents tested, only tranylcypromine had a statistically significant effect and stimulated transport. Of the serotonin receptor specific agents tested, those with 5HT1 activity most consistently affected transport. We conclude that serotonin, and perhaps histamine, are important modulators of the system that transports Tyr-MIF-1 and the enkephalins out of the CNS.

Animals↗

[Therapy of recurrent herpes simplex and its surveillance by MIF determination: with levamisole, BCG, urushiol and herpes antigen vaccine (author's transl)].

Thirty patients with recurrent herpes simplex and 6 controls were included in our study. Before initiation of treatment, during therapy with Levamisole, BCG, poison ivy and herpes antigen vaccine and, thereafter, MIF-determinations were performed. The latter test proved to be a useful parameter in evaluating the sensitivity against herpes infection, (and subsequent recurrent manifestations), and effect of therapy. Treatment with Levamisole, BCG and herpes antigen vaccine was successful. MIF-inhibition values paralleled the therapeutic effect in the Levamisole- and herpes antigen vaccine treated group, not however, in the BCG-treated patients

Antigens, Viral↗

Degradation of prolylleucylglycinamide (MIF) by mouse brain.

Prolylleucylglycinamide (MIF) at 1.0 mM concentration and pH 7.0 was hydrolyzed by mouse brain homogenate at a rate of 140 nmol/mg protein/hr. Nearly all of this activity can be accounted for by the action of two enzymes, both of which cleave Pro and Leu sequentially from the N-terminus of MIF. At pH 7.0 the predominant enzyme is arylamidase, inhibited by puromycin (1 mM) and Mn2+ (2.5 mM). At pH 8.5, in the presence of Mn2+, a second enzyme with a higher potential activity (570 nmol/mg protein/hr) was observed. While the arylamidase is primarily localized in the cytosol, the Mn2+-stimulated enzyme is equally divided between soluble and particulate fractions. Because of its ability to cleave leucinamide, its high pH optimum, and its Mn2+ dependence, it can be classified as a leucine aminopeptidase (LAP). In its substrate specifically and its preference for Mn2+ over Mg2+ it resembles the LAP from connective tissue more than that from other sources.

Aminopeptidases↗

The emerging role of MIF in septic shock and infection.

The protein mediator described originally as macrophage migration inhibitory factor (MIF) has been "re-discovered" recently to be both a novel pituitary hormone and a pro-inflammatory, macrophage-derived cytokine. Emerging studies indicate that MIF plays a pivotal role not only in endotoxic shock but also in the host response to a variety of acute and chronic infections.

Animals↗

Desensitization. V: Suppression of MIF production by lymphokine-activated macrophages.

The systemic injection of high doses of antigen into a previously immunized animal results in a state of transient anergy with respect to cell-mediated immune reactions. This phenomenon is known as desensitization. We have previously shown that desensitization is a multistage process. The initial 24-hr period is characterized by excessive lymphokine production with a failure to express delayed hypersensitivity reactions due to abolition of local chemotactic gradients. Subsequent stages of desensitization involve failure of lymphokine production in vivo. The results presented here demonstrate that lymphocytes obtained from immunized and desensitized animals later than 24 hr after desensitization are markedly suppressed in their ability to produce MIF. In addition, it was found that lymphokine-activated macrophages can suppress in vitro MIF production by lymphocytes from immune, nondesensitized animals. In vitro and in vivo activation of macrophages were equally effective. Thus, it is likely that at least one mechanism for the inhibition of lymphokine production in the post-24-hr period of desensitization, involves activation of a population of suppressor macrophages by lymphokines produced during the initial 24-hr period.

Animals↗

Cholecystokinin octapeptide (CCK-8), ceruletide and analogues of ceruletide: effects on tremors induced by oxotremorine, harmine and ibogaine. A comparison with prolyl-leucylglycine amide (MIF), anti-Parkinsonian drugs and clonazepam.

Cholecystokinin octapeptide (CCK-8), ceruletide (caerulein, CER) and 10 analogues of ceruletide, were studied in mice for antagonism of the tremors induced by harmine (5 mg/kg, s.c.), ibogaine (20 mg/kg, s.c.) and oxotremorine (0.2 mg/kg, s.c.). The following reference drugs were tested for comparison: prolyl-leucylglycine amide (MIF), atropine, haloperidol, biperiden, ethopropazine, trihexyphenidyl, methixene and clonazepam. All treatments were subcutaneous, the antagonists being given 10 min (in some trials 30 min) before the tremorogen. Tremorolytic potency (ED50) was calculated from dose-response curves. Against the tremors induced by either harmine or ibogaine, CCK-8 and ceruletide, as well as many of the analogues of ceruletide had greater tremorolytic potency than the reference drugs. Against oxotremorine, however, ceruletide and its most potent analogue, Nle8-CER (other analogues were not tested) were inactive and MIF showed very little effectiveness. Additional experiments on hypothermia and sedation as well as evaluation of previous studies on other central actions suggested that the tremorolytic effect of CCK-like peptides is independent of other central effects. The CCK-like peptides may play a physiological role in the regulation of extrapyramidal motor activity.

Alkaloids↗

Alpha-MSH and MIF-2 effects on serotonin levels and accumulation in various rat brain areas.

Levels as well as accumulation of serotonin (5-HT) were measured in various brain regions of the rat after administration of alpha-melanocyte-stimulating hormone (MSH) and Pro-Leu-Gly-NH2 (MIF-I). The method used in determining the serotonin measured both 5-OH-tryptamine (5-HT) and 5-methoxytryptamine (5-MT). No statistically significant changes in levels or accumulation of serotonin after pargyline injection were found when unoperated control rats were treated with either MSH or MIF-I. Similar treatment of hypophysectomized rats indicated that both peptides significantly (p less than 0.05) lowered serotonin accumulation only in the area of the frontal cortex; a similar but smaller, not statistically significant, decrease was seen in the hypothalamus and hippocampus of the hypophysectomized rat. Since only hypophysectomized rats were affected, no correlation between the behavioral effects of these peptides (which has been found to occur in both unoperated and hypophysectomized rats) and the biochemical changes could be made.

Animals↗

Increased acquisition of a complex appetitive task after MSH and MIF.

After daily injections of melanocyte stimulating hormone (MSH), MSH-release inhibiting factor (MIF), or diluent albino rats ran a 12 choice Warden maze for a palatable food reward. Rats receiving the hormones had shorter latencies and made fewer errors than controls during learning but, unlike results with simple tasks, there were no differences during extinction. The results demonstrated that both MSH and MIF-I could facilitate the acquisition of an appetitive task which seemed of sufficient complexity to emphasize differences in performance.

Animals↗

Influence of three short-chain peptides (alpha-MSH, MSH/ACTH 4-10, MIF-I on) dimensional attention.

Male, albino rats were treated with alpha-MSH, MSH/ACTH 4-10, MIF-I or a diluent control solution and then tested on a visual discrimination problem. Immediately after acquistion of the visual task the animals were tested with a spatial extradimensional shift problem. The animals treated with the MSH/ACTH 4-10 and MIF-I acquired the discrimination nonsignificantly faster than animals treated with alpha-MSH or a placebo. A subproblem analysis of the EDS behavior indicated that the peptides significantly improved performance probably by affecting attention.

Adrenocorticotropic Hormone↗

Investigations on alpha-MSH and MIF-1 effects on cyclic AMP levels in rat brain.

It has been suggested that the peptides alpha-metanocyte stimulating hormone (alpha-MSH) and MSH-release inhibitory factor (MIF-1) may alter adenosine-3', 5'-cyclic monophosphate (cAMP) metabolism [13,26]. Normal and hypophysectomized (hypoxed) rats were administered saline (controls IP daily X 3), alpha-MSH (80 mug/kg IP daily X 3) or MIF-1 (1 or 10 mg/kg IP daily X 3) and sacrificed 30 min after the third injection in a focused microwave oven (1.5 KW; 2-3 sec). Various brain areas were then assayed for cAMP levels after each treatment. The occipital cortex area was the only area to show consistent changes in both normal and hypoxed rats after alpha-MSH treatment. These findings were replicated for the occipital cortex in a second group of normal and hypoxed rats which were similarly treated. The results suggest a correlation between the rise in cAMP found and reported changes in visual acuity and attention in rats and human after treatment with alpha-MSH [8,14, 23].

Animals↗

Behavioral effects of melanocyte stimulating hormone release-inhibiting factor-1 (MIF-1).

Consideration of the isolation, structure, localization, and behavioral effects of melanocyte stimulating hormone release inhibiting factor (MIF-1) is followed by a review of its opiate antagonistic and clinical effects. Evidence pertaining to various hypotheses offered in explanation of these behavioral effects is examined and evaluated. It is concluded that MIF-1 affects behavior in many instances with possible antagonistic effects as well as clinical possibilities.

Animals↗

Rapid clinical effectiveness of MIF-I in the treatment of major depressive illness.

A double-blind 28 day study was conducted to compare the anti-depressant efficacy of MIF-I with that of imipramine. Twenty patients hospitalized with major depressive illness participated. Clinical responses were measured by using the Hamilton Depression Rating Scale, the Global Severity of Illness Scale, the Zung Self-Rating Depression Scale as well as the 100 mm line self-rating for depression. The results indicate that MIF-I was at least as effective as imipramine in this study, and that its anti-depressive effect was a rapid and often dramatic one.

Adult↗

17 beta Estradiol-induced increase in brain dopamine D-2 receptor: antagonism by MIF-1.

Animal behavioral and neurochemical studies implicate dopaminergic systems in the neurological sequelae induced by estrogen. In the present study, we demonstrated for the first time that MIF-1, a neuropeptide unrelated to classical dopamine agonists, when given prior to, concurrently with, and after 17 beta-estradiol, antagonized significantly the estrogen-induced increase in the density of dopamine D-2 receptor both in the striatum and the mesolimbic area of male rat brain. The current findings have implications for the prophylactic and therapeutic potential for MIF-1 in extrapyramidal motor disorders caused by estrogen imbalance in humans.

Animals↗