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At least 19 recordsLinked to original sources

PubMed1977

Synthetic melanocyte stimulating hormone release-inhibiting factor (MIF). Part III: effect of L-prolyl-N-methyl-D-leucyl-glycinamide and MIF on biogenic amine turnover.

The effect of the factor that inhibits the release of melanocyte stimulating hormone (MSH), i.e., L-prolyl-L-leucyl-glycinamide (MIF), and L-prolyl-N-methyl-D-leucyl-glycinamide, an analog, on brain norepinephrine (NE), dopamine (DA) and serotonin (5-HT) turnover was examined in rats. The analog (40 mg/kg i.p.), in a fashion similar to MIF (40 and 5 mg/kg i.p.), increased brain DA turnover; only MIF (40 mg/kg i.p.) increased endogenous DA levels. The analog (40 and 5 mg/kg i.p.) decreased brain NE turnover; MIF at the same doses was ineffective. Neither MIF nor the analog affected rat brain 5-HT turnover or the 5-HTP-induced behavioural syndrome in the mouse. These results indicate that the analog, like MIF, exerts effects on central catecholamine turnover. The different biochemical profile of the analog compared to MIF may be importance with regard to potential clinical use in the treatment of Parkinson's disease and depression.

5-Hydroxytryptophan↗

PubMed2026

Synovial short-lived plasma cells mediate adalimumab resistance in rheumatoid arthritis via MIF-CD74 axis-driven, partially TNF-α-independent inflammation.

OBJECTIVE: Synovial plasma cell infiltration predicts inadequate response to adalimumab in patients with rheumatoid arthritis (RA), yet the cellular and molecular mechanisms underlying this association remain unclear. This study aimed to dissect the functional heterogeneity of synovial plasma cells between adalimumab responders and non-responders at single-cell resolution, and to identify the molecular pathways driving treatment resistance. METHODS: This study was based on a prospective clinical cohort of 101 RA patients receiving adalimumab, from which synovial tissues of 8 patients (4 ACR20 responders and 4 non-responders) were profiled by 10x Genomics single-cell RNA sequencing (66,539 high-quality cells). A systematic ligand-receptor screening was performed to identify candidate signaling axes. Core findings were validated at four levels: an independent single-cell validation cohort (n = 4), external bulk RNA-seq cohorts (GSE15602, GSE47726), multiplex immunofluorescence on synovial tissues (n = 9 per group), and in vitro functional experiments using patient-derived peripheral blood monocyte-derived macrophages stimulated with recombinant human MIF under pharmacological intervention with adalimumab, the MIF inhibitor ISO-1, and an anti-CD74 neutralizing antibody. RESULTS: Plasma cells were significantly enriched in non-responder synovium, with a heterogeneous pattern characterized by quantitative accumulation of long-lived plasma cells (LLPCs) and functional dominance of short-lived plasma cells (SLPCs): SLPCs contributed 58.15% of total ribosomal module activity and preferentially overexpressed MIF. Systematic screening of 145 candidate ligand-receptor pairs identified MIF-CD74 as the only axis satisfying all four independent evidence layers. Tissue-level immunofluorescence confirmed that approximately 95% of synovial CD138+ plasma cells in non-responders co-expressed MIF, compared with approximately 45% in responders. In vitro, rh-MIF upregulated macrophage activation markers (CD74, CD80, CD86, HLA-DR) and induced IL-6 and TNF-α secretion. Adalimumab neutralized supernatant TNF-α but failed to suppress MIF-driven IL-6 and IL-1β activation, whereas ISO-1 and anti-CD74 effectively blocked MIF-induced effects at all levels examined. These findings were replicated in patient-derived PBMC macrophages. CONCLUSION: In adalimumab-resistant RA, a functionally active SLPC subset drives partially TNF-α-independent macrophage inflammation through the MIF-CD74 axis, representing a resistance pathway not fully addressed by anti-TNF therapy. Targeting MIF or CD74 blocked this axis in vitro, supporting MIF-CD74-directed precision intervention.

Adalimumab↗

PubMedDate not supplied

Striatal dopamine turnover and MIF-I.

Because of conflicting reports of the actions of the antiparkinsonian agent L-prolyl-L-leucyl-glycine amide (PLG, MIF-I) on the turnover of striatal dopamine (DA), this process was reinvestigated. In the present series of studies, it was found that neither our MIF-I (200 ng ICV) nor the MIF-I used by Versteeg et al. [25] was effective in altering the rate of decline of endogenous DA in the caudate nucleus of rats pretreated with alpha-methyl-p-tyrosine (300 mg/kg IP). In addition, our MIF-I (1 mg/kg IP) did not change endogenous dihydroxyphenylacetic acid (DOPAC) or homovanillic acid (HVA) in rat striatum. These studies indicate that MIF-I does not alter the turnover rate of DA in nigrostriatal neurons. It is possible that MIF-I or some substance released by MIF-I acts at a postsynaptic receptor site.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2026

MIF-CD74 axis facilitates MDSC infiltration in the tumor microenvironment of pancreatic ductal adenocarcinoma.

Immune checkpoint inhibitors show insufficient efficacy against pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment (TME) has a remarkable influence on responsiveness to cancer immunotherapy. The aim of this study was to investigate immunosuppressive characteristics of TME in PDAC tissues. The flow cytometry (FCM) of PDAC surgical specimens revealed that the profile of tumor-infiltrating leukocytes was classified into myeloid cell- and T-cell-dominant subtypes; the myeloid subtype was associated with poorer patient outcomes. Myeloid-derived suppressor cells (MDSCs) showed the highest hazard ratio among various myeloid cell types. Single-cell RNA sequencing and FCM revealed that most MDSCs, but not lymphocytes, in PDAC tissues characteristically express CD74. Macrophage migration inhibitory factor (MIF), a CD74 ligand, was highly expressed in cancer-associated fibroblasts (CAFs) and cancer cells. Spatial transcriptomics demonstrated that the MIF-CD74+ myeloid cell interaction was recognized in CAF-dominant areas in PDAC tissue. CAFs expressing immune suppressor molecules such as MFAP5 and LRRC15 were consistent with MIF+ CAFs. Furthermore, MIF+ CAFs enhanced the migratory activity of MDSCs and promoted MDSC induction and activation. In the murine model, MDSCs were significantly increased in MIF-expressing PDAC tumors, as were CD74+ M-MDSCs per M-MDSC, confirming in vivo interaction between CD74 and MIF. MDSCs play a crucial role in creating an immunosuppressive TME in PDAC; the MIF-CD74 axis drives interactions between MDSCs and CAFs.

Humans↗

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↗

PubMed1979

Effects of MIF-I and melatonin on novelty-induced defecation and associated plasma 11-OHCS and brain catecholamines.

In two experiments the effects were investigated of MSH-inhibiting factor-I (MIF-I) and of Melatonin on step-down latencies, defection, plasma 11-OHCS levels, whole brain DA and whole brain NE concentrations on Days 1, 3 and 5 of novelty exposure. Treatment with MIF-I led to a significant habituation of novelty-induced defecation over 5 days, whereas plasma 11-OHCS level was reduced only on Day 1. The concentrations of whole brain DA and whole brain NE also showed a significant increase over days of MIF-I and novelty treatment. Melatonin treatment, on the other hand, significantly inhibited novelty-induced defecation and reduced plasma 11-OHCS level on Day 5 of novelty exposure. Melatonin treatment led to a significant increase of whole brain DA in animals exposed to novelty for 5 days. Neither MIF-I nor Melatonin was found to significantly affect the step-down activity of treated animals. The overall results suggested a possible relationship between novelty-induced defecation and brain DA levels of MIF-I and Melatonin treated animals.

11-Hydroxycorticosteroids↗

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↗

PubMed2026

Stage-specific ROMO1 in rheumatoid arthritis: predictive immune insights into the MIF pathway and HLA-DR/IL2RA axis via integrated GWAS, transcriptomic, single-cell, and spatial profiling.

Emerging evidence links reactive oxygen species modulator 1 (ROMO1), a key mitochondrial ROS regulator, to rheumatoid arthritis (RA) pathogenesis. However, its exact mechanism remains elusive given the conflicting evidence about its specific function. We used a four-level integrative framework combining multi-omics data and literature‑supported mechanistic inference. At the genetic level, Mendelian randomization (MR) was performed to explore potential causal relationships between ROMO1, IL2RA, HLA-DR, MIF, and RA risk, followed by differential expression analysis and machine learning-based feature selection to identify key mROS genes. The temporal expression dynamics of ROMO1 were assessed in RA progression. At the cellular and tissue levels, we integrated single-cell RNA sequencing and spatial transcriptomics to map cell-type-specific expression and synovial localization of ROMO1-related immune cells and pathways. Finally, our multi-omics findings were contextualized with literature-supported mechanistic inference. (1) MR results were consistent with a potential protective effect of ROMO1 on RA (OR = 0.52) and its potential regulation of risk factors IL2RA (OR = 0.46) and HLA-DR (OR = 0.40). Conversely, IL2RA (OR = 1.42), HLA-DR (OR = 1.88), and MIF (OR = 1.17) were positively associated with RA risk. Additionally, ROMO1 was identified as a top candidate diagnostic predictor with stage-specific dynamics: downregulated in the early but upregulated in the late/remission stages. (2) Single-cell RNA sequencing showed ROMO1's cell-specific expression in CD14+ HLA-DR+ CD74+ monocytes and CD4+ IL2RA+ T cells. Cell communication analysis further suggested that these cells may participate in MIF pathway regulation. Spatial transcriptomics subsequently identified that ROMO1-related cells localized to synovial pathological regions, with MIF pathway changes correlated with RA progression. (3) Finally, literature-supported mechanistic inference suggests that ROMO1 may modulate mROS levels to promote anti-inflammatory M2 macrophage polarization, which could theoretically contribute to reduced systemic inflammation and the alleviation of multi-organ decline in RA. This integrated multi-omics investigation, supported by literature-based mechanistic inference, suggests ROMO1 as a stage-dependent biomarker candidate and potential immune regulator in RA.

Humans↗

PubMed2025

MIF as an oncogenic driver of low-heterogeneity melanomas.

Identifying targets involved in tumor evolution and immune escape is an active area of research in oncology. Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine that promotes transformed cell proliferation and survival, and generates a tumor-permissive immune landscape of immunosuppressive myeloid and T cells. Shvefel and colleagues have identified a key role for MIF in tumor progression in melanoma clones with low tumor heterogeneity. These findings provide important insights into the potential therapeutic utility of MIF antagonists and support ongoing research to utilize MIF pathway inhibitors for improved therapeutic outcomes.

Animals↗

PubMed1976

A comparison between a melanocyte-stimulating hormone inhibitory factor (MIF-I) and substances known to activate central dopamine receptors.

The tripeptide, prolyl-leucyl glycine amide, a melanocyte-stimulating hormone inhibitory factor (MIF-I), which has been reported to be effective in improving symptoms of Parkinson's disease, has been compared with drugs known to activate dopamine receptors in rat and mouse brain. Unlike apomorphine, amphetamine and amantadine it was incapable of producing sterotyped behaviour in the rat and unlike 1-dopa it was also ineffective in rats pretreated with the monoamineoxidase inhibitor mebanazine. Neither did it potentiate apomorphine nor amphetamine in this test. MIF-I did not antagonise chlorpromazine-induced loss of locomotor activity in mice, an effect which was antagonised by apomorphine, amphetamine and amantadine. Chlorpromazine hypothermia in the mouse was antagonised by 1-dopa but not by MIF-I; similar findings were obtained in reserpine-pretreated mice. These results suggest that the reported beneficial effect of MIF-I in Parkinson's disease is unlikely to be due to an interaction with dopamine systems in the brain.

Amantadine↗

PubMedDate not supplied

Alpha-MSH and MIF-I effects on catecholamine levels and synthesis in various rat brain areas.

Attempts were made to find a biochemical correlate with previously observed behavioral alterations after administration of alpha-melanocyte-stimulating hormone (MSH) and MSH release-inhibiting factor (MIF-I). Brains of intact and hypophysectomized (hypox) rats were analyzed for endogenous catecholamine levels and the disappearance rate of endogenous norepinephrine (NE) after treatment with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). The studies undertaken show the following: (1) After the injection of MSH (100 mug/kg IP daily x 3) and AMPT, samples in different groups of intact and hypox rats were taken at 0, 1, 2, 4 and 6 hrs in 7 different brain areas. In the mid-brain area for the intact group of rats, the rate of disappearance of NE was faster and for the hypox rats it was slower than the rate for control rats not treated with the peptides. NE levels in the same area at time 0 were 11 percent lower than controls in hypox rats and unchanged in unoperated animals. (2) After the injection of MIF-I (20 mg/kg IP daily x 3) in similar experiments as with MSH, a reduced rate (p less than 0.05) of NE disappearance for the first 4 hr and an increased rate (p less than 0.05) of NE disappearance for the last 2 hr of the experiments occurred for both the intact and hypox rats in the mid-brain area where endogenous NE levels were lowered by 11 and 12 percent at 0 min. In no other brain areas were alterations in NE breakdown found in both the intact and hypox rat groups. Behavioral changes have been found previously under similar experimental conditions in both intact and hypox rats. (3) Rates of dopamine disappearance in experiments similar to those described for NE disappearance indicated that in the striatal brain area no change was found in the intact rats after either MSH or MIF-I, whereas a decrease in DA disappearance was found for hypox rats during the six hour experimental period only after MSH. The results indicate that a correlation between behavioral changes, rates of disappearance and endogenous levels of NE in the mid-brain area may occur after MIF-I at the times examined but that a similar correlation for MSH did not appear likely.

Animals↗

PubMed1978

Dose-related biphasic effect of prolyl-leucyl-glycinamide (MIF-I) in depression.

Five of 8 patients with unipolar or bipolar endogenous depressions taking prolyl-leucyl-glycinamide (MIF-I), 75 mg/day, showed substantial improvement within a few days of beginning treatment compared with similar improvement in only 1 of 10 receiving 750 mg/day of MIF-I and only 1 of 5 patients taking placebo. The lower dose of MIF-I was associated with significantly greater improvement than both the higher dose and placebo on all of the rating scales used. The authors suggest that an even lower dose of MIF-I, on the order of 0.1 mg/kg, may have a greater effect as an antidepressant.

Adult↗

PubMed1977

Synthetic MIF analogues. Part II: Dopa potentiation and fluphenazine antagonism.

A comparison is described between the activity of the melanocyte-stimulating hormone release inhibiting factor (MIF) and those of five synthetic tripeptide analogues of MIF. The comparison was based upon the ability of the compounds to potentiate the behavioral effects of L-dopa in mide and to antagonize fluphenazine-induced catalepsy in rats. Three of the tripeptides potentiated L-dopa in a manner similar to that of MIF. All of the synthetic analogues antagonized fluphenazine after a single dose although their potency and their duration of action differed. MIF was active in the latter test only following chronic administration. The possible mechanism of action and the potential clinical applicability of the tripeptides are briefly discussed.

Animals↗

PubMed1978

[The influence of MIF (melanocyte-stimulating hormone-release inhibiting factor) on psychomotor function and mood in parkinsonian patients. Preliminary report (author's transl)].

In 12 parkinsonian patients aged from 40--76 years the L-dopa-potentiating effect of MIF was investigated using a doubleblind crossover design. MIF was given i.v. in a dose of 200 mg. The following psychological tests were carried out 4 times after the injection of MIF at hourly intervals: Purdue pegboard, Minnesota-Rate of manipulation test, 2-key-tapping, simple and complex reaction time and a state of well-being scale. The results revealed a marked effect on finger dexterity, drive and complex reaction time. That means MIF does not only lead to an improvement of psychomotor performance but also of cognitive functions. In contrast thereto the influence on the state of well-being was less impressive.

Adult↗

PubMed1977

On the optimal dosage of Pro-Leu-Gly-NH2 (MIF) in neuropharmacological tests and clinical use.

Pro-Leu-Gly-NH2 (MIF) inhibits the tremor induced by oxotremorine. Objective measurement of this tremor permits the drawing of a dose-effect curve. The inhibitory effect of the peptide increases linearly with increasing doses until an optimum is reached (between 30 and 40 mg/kg i.p.). At still higher doses the peptide is inactive. The same phenomenon is observed with analogues of MIF. This finding may have important bearings on the interpretation of clinical and experimental data obtained with MIF.

Animals↗

PubMed1976

MIF, TRH, and simian social and motor behavior.

MSH-release-inhibiting factor (MIF) and thyrotropin-releasing hormone (TRH) both have been reported to modify mood and activity in man. These two hypothalamic peptides were given intramuscularly across a 1000-fold dose range to 5 juvenile male M. nemestrina monkeys living in a social group. Motor activity was recorded automatically, and an observer counted various social behaviors. MIF increased motor activity for up to 11 hr. It decreased quiet foraging behavior, but did not change behaviors of social interaction. TRH did not stimulate motor behavior; high doses strongly suppressed it and produced apparent somatic distress. TRH increased behaviors of quiet rest and association and decreased environment exploration and low-intensity dominance behaviors. The lowest dose of TRH increased social play. Two monkeys showed repetitive, stereotyped behaviors even in baseline observations, and certain doses of TRH and MIF may have increased the frequency of these behaviors.

Animals↗

PubMed2026

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↗

PubMed1979

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↗