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PubMed2004

A Tyr-W-MIF-1 analog containing D-Pro2 acts as a selective mu2-opioid receptor antagonist in the mouse.

The antagonistic properties of Tyr-d-Pro-Trp-Gly-NH(2) (d-Pro(2)-Tyr-W-MIF-1), a Tyr-Pro-Trp-Gly-NH(2)(Tyr-W-MIF-1) analog, on the antinociception induced by the mu-opioid receptor agonists Tyr-W-MIF-1, [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), Tyr-Pro-Trp-Phe-NH(2) (endomorphin-1), and Tyr-Pro-Phe-Phe-NH(2) (endomorphin-2) were studied in the mouse paw-withdrawal test. d-Pro(2)-Tyr-W-MIF-1 injected intrathecally (i.t.) had no apparent effect on the thermal nociceptive threshold. d-Pro(2)-Tyr-W-MIF-1 (0.1-0.4 nmol) coadministered i.t. showed a dose-dependent attenuation of the antinociception induced by Tyr-W-MIF-1 without affecting endomorphin- or DAMGO-induced antinociception. However, higher doses of d-Pro(2)-Tyr-W-MIF-1 (0.8-1.2 nmol) significantly attenuated endomorphin-1- or DAMGO-induced antinociception, whereas the antinociception induced by endomorphin-2 was still not affected by d-Pro(2)-Tyr-W-MIF-1. Pretreatment i.t. with various doses of naloxonazine, a mu(1)-opioid receptor antagonist, attenuated the antinociception induced by Tyr-W-MIF-1, endomorphin-1, endomorphin-2, or DAMGO. Judging from the ID(50) values for naloxonazine against the antinociception induced by the mu-opioid receptor agonists, the antinociceptive effect of Tyr-W-MIF-1 is extremely less sensitive to naloxonazine than those of endomorphin-1 or DAMGO. In contrast, endomorphin-2-induced antinociception is extremely sensitive to naloxonazine. The present results clearly suggest that d-Pro(2)-Tyr-W-MIF-1 is the selective antagonist to be identified for the mu(2)-opioid receptor in the mouse spinal cord. d-Pro(2)-Tyr-W-MIF-1 may also discriminate between Tyr-W-MIF-1-induced antinociception and the antinociception induced by endomorphin-1 or DAMGO, all of which show a preference for the mu(2)-opioid receptor in the spinal cord.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1976

Partial characterization of murine migration inhibitory factor (MIF).

These studies describe the production of murine migration inhibitory factor (MIF)3 in sufficient quantities to allow its partial characterization by physiochemical and enzymatic methods. MIF was obtained from murine spleen cell cultures (C57BL/6 strain) stimulated with concanavalin A (Con A). Characterization of murine MIF was performed using Sephadex G-100 gel chromatography, isopycnic centrifugation in a CsCl density gradient, polyacrylamide disc electrophoresis, heat stability, and enzymatic treatment. MIF-containing and control fractions were assayed on normal C57BL/6 peritoneal exudate cells by using a microcapillary tube assay. Peak MIF activity was found in a Sephadex G-100 fraction containing molecules the size of albumin and slightly smaller, molecular weight 67,000 to 48,000. Murine MIF was stable to heating at 56 degrees C for 30 min but lost its activity at 80 degrees C for 30 min. Incubation of G-100 fractions containing MIF with water insoluble chymotrypsin destroyed the activity of MIF, indicating its protein nature. CsCl density gradient centrifugation revealed that murine MIF had a buoyand density greater than protein, consistent with its being a glycoprotein. Further, when subjected to disc electrophoresis on polyacylamide gels, murine MIF migrated in a region cathodal to albumin. Thus, mitogen stimulation of murine spleen cells produced MIF in quantities which allowed its partial characterization and purification, and its comparison with human and guinea pig MIF; this makes it feasible to analyze the role of murine MIF in cellular immunity and in its relationship to lymphocyte mediators which regulate humoral immune responses.

Animals↗

PubMed2004

Effects of Tyr-MIF's family of peptides on immobilization stress-induced antinociception in rats.

UNLABELLED: The Tyr-MIF-1 family of peptides includes MIF-1, Tyr-MIF-1, Tyr-W-MIF-1 and Tyr-K-MIF-1, which have been isolated from bovine hypothalamus and cortex of human brain. Data in the literature suggest that peptides of Tyr-MIF-1's family have opioid-like and anti-opioid actions. All these peptides interact with opioid receptors and in addition bind to non-opiate sites specific for each of the peptides and able to inhibit the expression of some forms of stress-induced analgesia (SIA) in various species. AIM: To examined the effects of the Tyr-MIF-1's peptides on immobilization stress-induced antinociception. METHODS: Tyr-MIF-1's peptides were given to male Wistar rats intraperitoneally before or after 1 hour of restraint. The changes in the mechanical nociceptive threshold of the animals were measured by the Randall-Selitto paw pressure test. RESULTS: Immobilization of the rats increased the pain threshold at least 1 h. Tyr-MIF-1's peptides have contrasting effects on immobilization stress-induced antinociception in paw-pressure test in rats. When administered before immobilization procedure they potentiated the immobilization stress-induced antinociception, while if given after immobilization, they reduced it. Antinociceptive effects of Tyr-MIF-1, Tyr-W-MIF-1 and Tyr-K-MIF-1 were reduced in condition of stress. CONCLUSION: Tyr-MIF-1's peptides exerted antiopioide effects under condition of stress in paw-pressure test. These antiopioide effects were more pronounced when peptides were injected after stress exposure.

Analysis of Variance↗

PubMed1991

Macrophage migration inhibitory factor (MIF) produced by a human T cell hybridoma clone.

A macrophage migration inhibitory factor (MIF) was purified to homogeneity from the serum-free culture supernatant of a human T cell hybridoma clone called F5. This clone was established by means of somatic fusion, using the emetine-actinomycin D selection method, and produced a large amount of MIF. The MIF activity in the culture supernatant of F5 cells was not due to contaminating interferon-gamma (IFN-gamma), which is known to possess MIF activity. Furthermore, other known cytokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF), were also revealed to have MIF activity, but our MIF was different from these known factors. F5 cells produced two species of MIF that could be separated on a phenyl-Sepharose column. MIF-1 (the more hydrophilic species of the two) was purified to homogeneity by sequential hydrophobic chromatography, ion-exchange chromatography, dye ligand affinity chromatography, and high-performance liquid chromatography (HPLC) on ion-exchange and reverse-phase columns. Finally, 4600-fold enrichment, as to specific activity, of MIF-1 was achieved. The purified MIF-1 was digested with endoproteinase Lys-C into some peptide fragments and the amino acid sequences of the peptides obtained were determined. No sequence identity between our MIF-1 and other proteins was observed. Then, antibodies were raised against a peptide synthesized according to the determined amino acid sequence. They specifically reacted with MIF-1 and reduced its migration inhibitory activity. Based on these results, we conclude that the determined amino acid sequence was certainly that of MIF-1.

Amino Acid Sequence↗

PubMed1986

Inhibition of macrophage migration by a factor from ascites fluids of ovarian cancer patients. II. Production and characterization of an anti-MIF antibody.

A macrophage migration inhibition factor (OC-MIF) has been isolated from ascites fluid of ovarian cancer patients by affinity chromatography on L-fucose-Sepharose 6B, and characterized biochemically. OC-MIF activity was purified approximately 10 000-fold as compared to the starting material. It exhibits molecular heterogeneity with respect to net charge and molecular weights. Compared to it, purified and radioiodinated OC-MIF is fairly homogeneous and contains a major protein component with a molecular mass of about 45 kD, and two isoelectric points of 3.0-4.0 and about 5.0. Rabbits were immunized with the highly purified MIF material and an antiserum was prepared and was used to prepare immunoadsorbent beads. Beads made with anti-OC-MIF antiserum, but not with rabbit control serum, could remove specifically OC-MIF activity and showed weak reactivity towards Con A induced MIF. Using a radioimmunoassay (RIA) anti-OC-MIF antiserum reacts with OC-MIF and also with Con A induced MIF. This antigenic relationship between conventional MIF and OC-MIF and common biochemical properties suggest that the two mediator substances are very similar and may, perhaps, be identical. Furthermore, the possibility to determine various MIF activities by means of RIA was investigated.

Antibodies↗

PubMed1997

TNF-alpha up-regulates renal MIF expression in rat crescentic glomerulonephritis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a potent proinflammatory mediator that participates in the pathogenesis of endotoxemia and experimental crescentic glomerulonephritis. However, very little is known about how MIF production is regulated in disease. We therefore examined whether tumor necrosis factor alpha (TNF-alpha), a known inducer of MIF expression by macrophages in vitro, up-regulates local and systemic MIF expression in a macrophage-mediated rat model of crescentic glomerulonephritis. MATERIALS AND METHODS: Anti-glomerular basement membrane (GBM) glomerulonephritis was induced in groups of six primed rats. Animals were treated with 1 mg/kg soluble TNF-alpha receptor (TNFbp) or saline from the time of disease induction until they were killed on Days 1, 7, or 14. Renal MIF expression was assessed by in situ hybridization, immunohistochemistry, and ELISA, and compared with macrophage accumulation and indices of renal damage. RESULTS: Although TNFbp treatment on Day 1 of the disease had only a partial effect upon the up-regulation of glomerular MIF expression, on Days 7 to 14 it almost completely abrogated the increase in glomerular and interstitial MIF mRNA and protein expression. In addition, TNFbp treatment significantly inhibited MIF secretion by cultured glomeruli and reduced serum MIF levels. The inhibition of renal MIF expression was paralleled by a significant inhibition of glomerular and interstitial macrophage infiltration (p < 0.001 versus saline treated), a significant suppression of renal injury (proteinuria and serum creatinine), and a marked reduction in histologic damage (glomerular hypercellularity, crescent formation, and interstitial fibrosis; all p < 0.01 versus saline treated). CONCLUSIONS: This study demonstrates for the first time that TNF-alpha up-regulates local MIF expression by both infiltrating macrophages and resident kidney cells in rat crescentic glomerulonephritis. In addition, TNF-alpha regulates systemic MIF production. Thus, TNF-alpha, together with MIF, may play a pathological role in immunologically induced renal disease.

Animals↗

PubMed1998

Specific reduction of insulin disulfides by macrophage migration inhibitory factor (MIF) with glutathione and dihydrolipoamide: potential role in cellular redox processes.

The molecular mechanism of action of MIF, a cytokine that plays a critical role in the host immune and inflammatory response, has not yet been identified. We recently demonstrated that MIF is an enzyme that exhibits oxidoreductase activity by a cysteine thiol-mediated mechanism. Here we further investigated this function by examining the reduction of insulin disulfides by wild-type human MIF (wtMIF) using various substrates, namely glutathione (GSH), dihydrolipoamide, L-cysteine, beta-mercaptoethanol and dithiothreitol. The activity of wtMIF was compared to that of the relevant cysteine mutants of MIF and to two carboxy-truncated mutants. Only GSH and dihydrolipoamide were found to serve as reductants, whereas the other substrates were not utilized by MIF. Reduction of insulin disulfides by MIF was closely dependent on the presence of the Cys57-Ala-Leu-Cys60 (CALC) motif-forming cysteines C57 and C60, whereas C81 was not involved (activities: 51+/-13%, 14+/-5%, and 70+/-12% of wtMIF, respectively, and 20+/-3% for the double mutant C57S/C60S). Confirming the notion that the activity of MIF was dependent on the CALC motif in the central region of the MIF sequence, the C-terminal deletion mutants MIF(1-105) and MIF(1-110) were found to be fully active. The favored use of GSH and dihydrolipoamide indicated that MIF may be involved in the regulation of cellular redox processes and was supported further by the finding that MIF expression by the cell lines COS-1 and RAW 264.7 was significantly induced upon treatment with the oxidant hydrogen peroxide.

Amino Acid Sequence↗

PubMed2000

Macrophage migration inhibitory factor (MIF) in bronchial asthma.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine favouring the secretion of TNFalpha and IL-8 and counteracts anti-inflammatory effects of corticosteroids. Airways inflammation is a central feature of bronchial asthma and is characterized by the accumulation of eosinophils. OBJECTIVE: The aim of this study was to investigate whether MIF is related to asthma symptoms and eosinophil accumulation in the airways. METHODS: Serum MIF levels were measured by an enzyme-linked immunosorbent assay in 44 healthy subjects and 44 asthmatics. Levels of MIF in induced sputum were measured in 10 healthy subjects and 15 asthmatics. Levels of eosinophil cationic protein (ECP) in induced sputum were measured by a radioimmunosorbent assay. Fluorescence double immunostaining was conducted to examine cellular source and localization of MIF. RESULTS: Serum MIF levels were significantly increased in asthmatic patients compared with age and sex-matched control subjects. Symptomatic patients had a higher MIF level than asymptomatic patients. Induced sputum obtained from asthmatics contained higher levels of MIF than those from control subjects. MIF levels in induced sputum were correlated with ECP levels in induced sputum. MIF was colocalized with eosinophil peroxidase staining in the cytoplasm of sputum cells. CONCLUSION: Increased MIF levels are associated with asthma symptoms and one of the cellular sources of MIF in the airways are eosinophils.

Adult↗

PubMed1999

An essential role for macrophage migration inhibitory factor (MIF) in angiogenesis and the growth of a murine lymphoma.

BACKGROUND: Macrophage migration inhibitory factor (MIF) has been shown to counterregulate glucocorticoid action and to play an essential role in the activation of macrophages and T cells in vivo. MIF also may function as an autocrine growth factor in certain cell systems. We have explored the role of MIF in the growth of the 38C13 B cell lymphoma in C3H/HeN mice, a well-characterized syngeneic model for the study of solid tumor biology. MATERIALS AND METHODS: Tumor-bearing mice were treated with a neutralizing anti-MIF monoclonal antibody and the tumor response assessed grossly and histologically. Tumor capillaries were enumerated by immunohistochemistry and analyzed for MIF expression. The effect of MIF on endothelial cell proliferation was studied in vitro, utilizing both specific antibody and antisense oligonucleotide constructs. The role of MIF in angiogenesis also was examined in a standard Matrigel model of new blood vessel formation in vivo. RESULTS: The administration of anti-MIF monoclonal antibodies to mice was found to reduce significantly the growth and the vascularization of the 38C13 B cell lymphoma. By immunohistochemistry, MIF was expressed predominantly within the tumor-associated neovasculature. Cultured microvascular endothelial cells, but not 38C13 B cells, produced MIF protein and required its activity for proliferation in vitro. Anti-MIF monoclonal antibody also was found to markedly inhibit the neovascularization response elicited by Matrigel implantation. CONCLUSION: These data significantly expand the role of MIF in host responses, and suggest a new target for the development of anti-neoplastic agents that inhibit tumor neovascularization.

Animals↗

PubMed2001

Macrophage migration inhibitory factor (MIF) modulates innate immune responses induced by endotoxin and Gram-negative bacteria.

Discovered in the early 1960s as a T-cell cytokine, MIF has emerged to be an important mediator of the innate immune system. MIF was identified recently to be released by a vast array of cells, including monocytes/macrophages, T-cells, B-cells, endocrine cells and epithelial cells in response to infection and stress. Bacteria, microbial toxins and cytokines have been shown to be powerful inducers of MIF secretion by macrophages. MIF stimulates the expression of pro-inflammatory mediators by immune cells and functions to counterbalance the anti-inflammatory and immunosuppressive effects of glucocorticoids. Like TNF and IL-1, MIF plays an important role in host responses to infection. Recombinant MIF was found to exacerbate lethal endotoxemia or bacterial sepsis when co-injected with LPS or Escherichia coli in mice. Conversely, MIF knockout mice or mice treated with anti-MIF antibodies were protected from shock induced by LPS, staphylococcal exotoxins or bacterial peritonitis, even when anti-MIF therapy was started after the onset of infection. Given the central role played by MIF in innate immune responses against microbial pathogens and in the regulation of inflammatory responses, pharmacological modulation of MIF production or neutralization of MIF activity could have broad clinical applications and may offer new treatment options for the management of patients with severe sepsis or septic shock.

Animals↗

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↗

PubMed1990

Stereospecific transport of Tyr-MIF-1 across the blood-brain barrier by peptide transport system-1.

Previous studies have suggested that peptide transport system-1 (PTS-1), the saturable system that transports Tyr-MIF-1, the enkephalins, and related peptides out of the central nervous system (CNS), exhibits stereospecificity. In the present studies, we showed that 125I-L-Tyr-MIF-1, but not 131I-D-Tyr-MIF-1, was cleared from the CNS more rapidly than could be accounted for by nonspecific mechanisms. Such clearance was inhibited by a 1.0 nmol dose of L-Tyr-MIF-1, but not by D-Tyr-MIF-1. Neither L- nor D-Tyr-MIF-1 altered the much lower clearance of I-D-Tyr-MIF-1 from the brain. Radioactivity recovered from the vascular space after the injection of 125I-Tyr-MIF-1 into the lateral ventricle of the brain eluted by HPLC primarily as intact peptide, demonstrating that most of the Tyr-MIF-1 was not degraded during transport. By contrast, the nonsaturable unidirectional influx of Tyr-MIF-1 into the CNS did not distinguish between the isomers. These studies confirm and extend the observations that Tyr-MIF-1 is transported out of the CNS by a saturable, stereospecific transport system as an intact peptide while the influx into the CNS is by a nonsaturable mechanism that does not distinguish between the isomers.

Animals↗

PubMed2006

Reduction of the aortic inflammatory response in spontaneous atherosclerosis by blockade of macrophage migration inhibitory factor (MIF).

Atherosclerosis is an inflammatory response of the arterial wall to "injury", which is prominently driven by cytokines. The inflammatory mediator macrophage migration inhibitory factor (MIF) is a unique cytokine that was recently associated with atherogenesis. Here, we have investigated whether MIF has a role in spontaneous atherosclerosis by studying apolipoprotein E-deficient (ApoE(-/-)) mice treated with neutralizing anti-MIF monoclonal antibody and comparison with isotype IgG-treated controls. After 14 weeks, the aortas and heart valves were analyzed for inflammatory status, macrophage content and plaque areas. MIF expression in the aortic wall was elevated upon spontaneous atherogenesis, with foam cells representing a major source. Of note, MIF blockade led to a marked reduction in intimal Mac-1-positive macrophages. Similarly, treatment with anti-MIF antibody led to a reduction of a variety of inflammatory mediators typically associated with atherosclerosis including the circulating levels of fibrinogen, MIF and IL-6. Importantly, the local aortic expression of ICAM-1, MMP-2, TNF, IL-12, and CD40L was reduced by MIF blockade, as were the levels of the phospho-c-Jun and C/EBPbeta transcription factors. The observed strong reduction of inflammatory parameters by anti-MIF treatment was associated with a small, yet non-significant, reduction in aortic plaque area. Thus, although MIF's role is not directly linked to plaque volume expansion, in this mouse model of spontaneous atherogenesis, MIF plays an important role in intimal inflammation.

Animals↗

PubMed2006

MIF production by dendritic cells is differentially regulated by Toll-like receptors and increased during rheumatoid arthritis.

Macrophage migration inhibitory factor (MIF) is clearly associated with rheumatoid arthritis (RA) disease severity. However, the regulation of MIF during the course of RA has not been subjected to similar scientific scrutiny. The aim of our study was to investigate the role of various Toll-like receptors (TLRs) and inflammatory mediators on MIF production by dendritic cells (DCs) in healthy controls and RA patients. DCs were cultured from 12 healthy donors and 12 RA patients. Triggering via TLR mediated pathways was achieved using various TLR specific ligands alone or in combination: Pam3Cys for TLR2, LPS and recombinant extra domain A containing fibronectin for TLR4 and Poly(I:C) and R848 for TLR3 and TLR7, respectively. In addition, iDCs from healthy controls were incubated with various cytokines, RANKL and CD40L for 48 h. MIF levels were measured using an ELISA assay. Stimulation of DCs by TLR4 ligands resulted in higher MIF production compared to immature DCs from healthy controls (p<0.002) and RA patients (p<0.002). DCs from RA patients produced higher MIF levels than healthy controls both at the immature stage (p<0.04) as well after full maturation via TLR2 (p<0.04) and TLR4 (p<0.001) triggering. Incubation with TLR3 and TLR7 ligands resulted in a significantly decreased secretion of MIF in RA patients and controls. Simultaneous incubation of TLR4 with either TLR3 or TLR7 ligands resulted in a decrease of MIF secretion when compared to TLR4 stimulation alone. The secretion of MIF increased when DCs were stimulated with TNF-alpha, RANKL and CD40L. The secretion of MIF by dendritic cells is differentially regulated by TLRs. In addition, TNF-alpha, RANKL, and CD40L augment MIF production by DCs and thus play a potential role in the amplification of the inflammatory loop in RA.

Arthritis, Rheumatoid↗

PubMed2004

Macrophage migration inhibitory factor (MIF) in chinese amphioxus as a molecular marker of immune evolution during the transition of invertebrate/vertebrate.

Macrophage migration inhibitory factor (MIF) is an important cytokine related to host defenses and autoimmune diseases. Here, we reported two full-length cDNA clones isolated from Chinese amphioxus (Branchiostoma belcheri tsingtaunese). Amino acid sequences analysis and structure prediction of these two molecules, called Bbt-MIF-I and Bbt-MIF-II, respectively, indicated that several conservative domains existed in the two amphioxus MIFs and their sequences were highly homologous to their counterparts of other species. Intriguingly, the Bbt-MIFs gene is present in multi-copy per haploid genome, which is very unusual compared with vertebrate's MIF gene given the known genome duplication theory. The genomic copy number, expression pattern of MIF gene and phylogenetic analysis of MIF proteins all suggested that a leap forward happened for MIF gene during the evolution from invertebrate to vertebrate. Considering the crucial role of MIF in innate immunity, MIF might serve as one of key molecular markers of evolution of immune system.

Amino Acid Sequence↗

PubMed2004

Macrophage migration inhibitory factor: identification of the 30-kDa MIF-related protein in bovine brain.

Macrophage migration inhibitory factor (MIF) is a ubiquitous protein playing various immunologic, enzymatic, and hormonal roles. MIF was originally identified for its capacity to inhibit the random movement of macrophages in vitro. MIF is widely expressed in many tissues with particularly high levels in the nervous system. Using the reversed-phase HPLC, N-terminal microsequence analysis, and database searching, we have identified in bovine brain several MIF-like proteins. According to mass spectral analysis, the molecular masses for three of them were determined as 12,369.2, 12,299.7, and 9,496.2 Da. In addition, we have identified another MIF-related protein (29,568.9 Da) by Western blotting using anti-MIF antibody raised to MIF (having an apparent molecular weight of 12 kDa) isolated to homogeneity from bovine brain cytosol. The modified purification procedure was mainly based on exclusion- and ion-exchange chromatography. Using p-hydroxyphenylpyruvic acid as a substrate, we have demonstrated tautomerase activity of the isolated MIF. The N-terminal sequences for all MIF-like proteins were found to be identical. Several other higher molecular weight putative MIF-related proteins were also revealed in the bovine brain cytosol extract. A multifunctional nature of MIF is suggested to be a result of its occurrence in different oligomerization states in a wide variety of tissues and cells.

Amino Acid Sequence↗

PubMed2002

Macrophage migratory inhibitory factor (MIF) expression in acute graft-versus-host disease (GVHD) in allogeneic hemopoietic stem cell transplant recipients.

Graft-versus-host disease (GVHD) is a major complication after hemopoietic stem cell transplantation (HSCT), but its pathogenesis remains uncertain. Macrophage migratory inhibitory factor (MIF) is an important mediator in the allo-immune reaction during renal transplantation, yet its role in hemopoietic stem cell transplantation (HSCT) remains unexplored. This study investigated the potential role of MIF in acute graft-versus-host disease (aGVHD) following allogeneic HSCT. Forty-six randomly selected patients undergoing autologous or allogeneic HSCT were studied. Immunohistochemistry and in situ hybridization were performed to examine tissue MIF mRNA and protein expression on skin and colonic biopsy specimens. The associated T cell and macrophage activation was also studied by immunohistochemical studies. A semi-quantitative method was used to assess MIF staining, as well as T cell and macrophage staining. Serial blood samples were analyzed by ELISA for serum MIF levels. Immunohistochemistry and in situ hybridization performed in 15 skin and 19 colonic biopsies from 17 patients who developed moderate to severe aGVHD showed a significant increase in MIF mRNA and protein expression compared with normal controls (seven skin and five colonic biopsies). MIF was localized within the epidermis and the vascular area of skin, but diffusely expressed in the entire thickness of colon. Macrophage and T lymphocyte infiltration was confined to areas of strong MIF expression. Serial analysis by ELISA showed that only patients who developed aGVHD (n = 19) exhibited an increase (two- to three-fold) in serum MIF during HSCT, but not in the allogeneic HSCT recipients without aGVHD (n = 7) or those who received autologous HSCT (n = 8). In 14 out of 19 patients, serum MIF peaked before the onset of aGVHD. Local and systemic up-regulation of MIF expression is associated with the occurrence of acute GVHD. Its pathogenetic role remains to be further determined.

Acute Disease↗

PubMed2004

Antiopioid properties of the TYR-MIF-1 family.

The Tyr-MIF-1 family of peptides includes MIF-1, Tyr-MIF-1, Tyr-W-MIF-1 and Tyr-K-MIF-1, which have been isolated from bovine hypothalamus and human brain cortex. All these peptides interact with opioid receptors and in addition bind to non-opiate sites specific for each of the peptides. Data in the literature suggest that peptides of the Tyr-MIF-1 family (Tyr-MIF-1s) have antiopioid and opioid- like effects. It is known that some anti-opioid peptides (AOP) could reverse morphine-induced analgesia in rodents and men and able to inhibit the expression of some forms of stress-induced analgesia (SIA) in various species. We examined the effects of the Tyr-MIF-1 peptides (all in dose 1 mg/kg i.p.) in the male Wistar rats on morphine-induced analgesia in acute pain using the paw-pressure (PP) and the tail-flick (TF) tests and on immobilization stress-induced antinociception using the PP test. Our results showed that the Tyr-MIF-1 peptides significantly decreased the analgesic effect of morphine (1 mg/kg i.p.) in both tests used. Immobilization of the rats increased the pain threshold for at least 1 h. The Tyr-MIF-1 peptides reduced stress-induced antinociception in PP test. In conclusion, our findings indicate that Tyr-MIF-1s modulate the analgesic effects of morphine and SIA, which corresponds with the hypothesis about AOP mentioned above.

Animals↗