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PubMedDate not supplied

Isolation of a novel tetrapeptide with opiate and antiopiate activity from human brain cortex: Tyr-Pro-Trp-Gly-NH2 (Tyr-W-MIF-1).

A novel tetrapeptide, Tyr-Pro-Trp-Gly-NH2 (Tyr-W-MIF-1), was purified from extracts of frontal cortex of human brain tissue by several consecutive reversed-phase high performance liquid chromatographic steps followed by a radioimmunoassay originally developed for Tyr-Pro-Leu-Gly-NH2 (Tyr-MIF-1). Sequencing, mass spectrometric analysis, and comparison of its chromatographic behavior with that of the synthetic peptide confirmed the structure. Like Tyr-MIF-1, which was previously isolated from human brain tissue, Tyr-W-MIF-1 can inhibit the binding of 3H-DAMGO (selective for mu opiate receptors) to rat brain and can act as an opiate agonist as well as antagonist. Tyr-W-MIF-1 was a more potent opiate agonist than Tyr-MIF-1, the free acid of Tyr-W-MIF-1, and the structurally related hemoglobin-derived opiate peptide hemorphin-4 (Tyr-Pro-Trp-Thr) in the guinea pig ileum. Each of these peptides acted as opiate antagonists on the ileum from morphine-tolerant guinea pigs; the free acid of Tyr-W-MIF-1 was the most potent antagonist in inhibiting the activity of DAMGO. The results demonstrate the presence in human brain of a new member of the Tyr-MIF-1 family of biologically active peptides.

Amino Acid Sequence↗
PubMed1994

Delayed degradation of Tyr-MIF-1 in neonatal rat plasma.

Peptides like Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) that are administered during the neonatal period can result in biological effects persisting into the adult period. The possibility that Tyr-MIF-1 might have a prolonged half-life in neonatal blood was investigated by HPLC of plasma obtained from 4-day-old rat pups. More than half (65%) of the tritiated Tyr-MIF-1 incubated with neonatal rat plasma at 37 degrees C remained in intact form at 30 min compared with less than a quarter of the Tyr-MIF-1 incubated with adult rat plasma. The calculated half-life of the tetrapeptide incubated in neonatal plasma was 50.2 min, compared with 13.8 min for adult plasma (p < 0.01). The simultaneous addition of Tyr-MIF-1 tritiated on the Tyr and Tyr-MIF-1 tritiated on the Pro showed the formation of equal amounts of the free amino acids Tyr and Pro; this indicates that Tyr-MIF-1 is not a precursor of MIF-1 in neonatal rat plasma. The results show that the degradation of Tyr-MIF-1 is significantly delayed in plasma from neonatal rats, suggesting the possibility that the metabolism of other peptides and different types of compounds also may be delayed during the perinatal period.

Aging↗
PubMed1994

Extreme stability of Tyr-MIF-1 in CSF.

Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2), an endogenous brain peptide, was incubated at 37 degrees C in cerebrospinal fluid (CSF) from rats and the amount remaining in intact from determined by high performance liquid chromatography (HPLC). By 3 min, a time at which Tyr-MIF-1 had been considerably degraded by rat plasma, essentially no degradation of the tetrapeptide had occurred in CSF. Tyr-MIF-1 persisted in mainly intact form for the 8 days tested, with a calculated half-time degradation of 11.4 days. The simultaneous addition to CSF of equal amounts of Tyr-MIF-1 tritiated on the Tyr and Tyr-MIF-1 tritiated on the Pro facilitated determination of whether Tyr-MIF-1 serves as a precursor of MIF-1 (Pro-Leu-Gly-NH2) in CSF. This possibility was excluded by the findings that the primary metabolite was Tyr-Pro, with minimal and equal amounts of the free amino acids Pro and Tyr being formed, but no MIF-1. The results show the extreme stability of Tyr-MIF-1 in CSF and are consistent with a role for this peptide in the CNS.

Amino Acid Sequence↗
PubMed1993

Tyr-MIF-1 attenuates development of tolerance to spiperone-induced catalepsy in rats.

Because the tripeptide MIF-1 (Pro-Leu-Gly-NH2) is known to attenuate the effects of neuroleptic-induced catalepsy as well as neuroleptic-induced proliferation of dopamine (DA) receptors, we studied the related naturally occurring peptide, Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) for similar properties. Male rats were treated SC for 11 consecutive days with either the DA D1 receptor antagonist SCH 23390 HCl (0.50 mg/kg per day), the DA D2 receptor antagonist spiperone HCl (0.30 mg/kg per day), or vehicle. Half the rats were cotreated daily with Tyr-MIF-1 (1.0 mg/kg per day). The cataleptic effects of SCH 23390 were not altered by Tyr-MIF-1. Tolerance to SCH 23390-induced catalepsy did not develop during the 11-day treatment, and Tyr-MIF-1 had no effect on SCH 23390-induced catalepsy. However, tolerance developed to spiperone-induced catalepsy, and Tyr-MIF-1 attenuated this development of tolerance (p < 0.001). Locomotor and stereotyped activities of the DA D1 and D2 agonists, SKF 39393 (3.0 mg/kg) and quinpirole (3.0 mg/kg) were not affected by Tyr-MIF-1 after treatment with the DA antagonists was discontinued. Tyr-MIF-1 did not alter the Bmax or Kd for in vitro binding of [3H]SCH 23390 and [3H]spiperone to homogenates of the striatum. These findings indicate that Tyr-MIF-1 is able to selectively affect the development of receptor tolerance to a DA D2 receptor antagonist, and that this effect is unrelated to changes in affinity or numbers of D2 receptors.

Amino Acid Sequence↗
PubMed2006

Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1.

Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However, despite the compelling evidence that MIF is overexpressed in, and contributes to, the pathology of inflammatory and malignant diseases the mechanisms that contribute to exaggerated expression of MIF have been poorly described. Here we show that hypoxia, and specifically HIF-1alpha, is a potent and rapid inducer of MIF expression. In addition, we demonstrate that hypoxia-induced MIF expression is dependent upon a HRE in the 5'UTR of the MIF gene but is further modulated by CREB expression. We propose a model where hypoxia-induced MIF expression is driven by HIF-1 but amplified by hypoxia-induced degradation of CREB. Given the importance of MIF in inflammatory and malignant diseases these data reveal a HIF-1-mediated pathway as a potential therapeutic target for suppression of MIF expression in hypoxic tissues.

5' Untranslated Regions↗
PubMed2005

Role of macrophage migration inhibitory factor (MIF) in the skin.

Macrophage migration inhibitory factor (MIF) functions as a pleiotropic protein, participating in both inflammation and immune responses. MIF was originally discovered as a lymphokine involved in delayed type hypersensitivity and various macrophage functions, including phagocytosis, and tumor surveillance. Recently, MIF has been re-evaluated as a pro-inflammatory cytokine and identified as a pituitary-derived hormone, potentiating endotoxemia. MIF is ubiquitously expressed in various tissues, including the skin. Clinical evidence of increased MIF expression in inflammatory diseases supports this potential role of MIF in inflammation. In addition to its role in inflammation, MIF has been shown to exhibit growth-promoting activity, with anti-MIF antibodies effectively suppressing tumor growth and tumor-associated angiogenesis. This review presents the latest findings on the roles of MIF in the skin with regard to inflammation, the immune response, skin disease, tumorigenesis and cutaneous wound healing, and discusses its potential functions in various pathophysiological states.

Animals↗
PubMed1999

Peptide transport system-1 (PTS-1) for Tyr-MIF-1 and Met-enkephalin differs from the receptors for either.

Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) and Met-enkephalin share a saturable transport system (peptide transport system-1, PTS-1) across the blood-brain barrier but do not readily bind to each other's receptors. This information allows the unique opportunity to differentiate the transport protein(s) from the receptors for either peptide in brain endothelial cells. PTS-1 was studied in vitro by allowing radiolabeled Tyr-MIF-1 (125I-Tyr-MIF-1) to bind to the solubilized proteins of isolated murine brain microvessels in the presence or absence of potential inhibitors. Sephadex chromatography separated bound from free labeled peptide. The binding was saturable as shown by inhibition with increasing concentrations of unlabeled Tyr-MIF-1. 125I-Tyr-MIF-1 binding was not inhibited by an unrelated peptide or iodo-tyrosine. D-Tyr-MIF-1 had no effect, demonstrating the stereospecificity of the system. Met-enkephalin decreased the binding of 125I-Tyr-MIF-1 to 84.4% of total, whereas Leu-enkephalin was without effect. Agonists for the mu, delta, and kappa opiate receptors did not change the binding, indicating that the proteins which bound to 125I-Tyr-MIF-1 were not endogenous opiate receptors. The results indicate that, in vitro, Tyr-MIF-1 binds to brain microvessel proteins with characteristics similar to PTS-1.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2000

Multiprotein complexes present at the MIF motifs flanking the promoter of the human c-myc gene.

The activated c-myc allele in Burkitt's lymphoma is associated with a clustering of somatic mutations within a discrete domain of intron I that define protein recognition sequences, designated as myc intron factors (MIF-1, MIF-2 and MIF-3). We have previously shown that MIF-1 binding activity consists of two polypeptides, myc intron binding polypeptide (MIBP1) and RFX1. In the present study we identified two polypeptides, p105 and p115, and showed that these proteins give rise to a DNA-protein complex at the MIF-2 as well as the adjacent MIF-1 site. In addition, we demonstrated that all four proteins interact with a novel MIF-1 like motif upstream from the c-myc promoter region, designated 5'MIF. These data suggest a model, where the interactions of MIBP1/RFX1 and p105/p115 with the MIF-like sites may play a role in the promoter topology of the c-myc gene.

Burkitt Lymphoma↗
PubMed1999

Identification of macrophage migration inhibitory factor (MIF) in rat peripheral nerves: its possible involvement in nerve regeneration.

Macrophage migration inhibitory factor (MIF) is known as a pluripotent immunoregulatory cytokine involved in T-cell activation and inflammatory responses; however, no study on this protein in the peripheral nervous systems has been carried out. We here demonstrated for the first time expression of MIF mRNA and MIF protein in rat sciatic nerves by reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. Immunohistochemical analysis revealed positive staining of MIF, which was largely observed in Schwann cells. Furthermore, we examined MIF mRNA expression in the sciatic nerves by Northern blot analysis in the case of nerve transection. In both proximal and distal segments, the level of MIF mRNA started to increase 12 h after the nerve transection. The level remained high from 24 h up to day 7 after the injury. During the period from days 14 to 21, MIF mRNA sharply decreased to the pre-transection level. In immunohistochemistry, positive staining of MIF was largely observed in axons as well as non-neuronal cells in proximal segments at day 4 after transection. In the distal segments, contrastingly, endoneurial fibroblasts or Schwann cells migrating into neuronal fibers showed positive staining with Wallerian degeneration. Although the precise functions of MIF in the peripheral nerves remain to be elucidated, the present results could represent a major departure from the current state of knowledge, revealing a novel function in the degenerative-regenerative process.

Animals↗
PubMed2002

Inhibition of hematopoietic progenitor cell growth by Tyr-MIF, an endogenous opiate modulator, and its degradation products.

There is increasing evidence that neuronal factors can affect hematopoietic cell proliferation. Endogenous opioids with specificity for several opioid receptor classes were tested for their ability to inhibit murine and human hematopoietic progenitor cell proliferation. Tyr-MIF, an opioid tetrapeptide (H-Tyr-Pro-Leu-Gly-NH2), demonstrated a dose-dependent inhibition of colony formation at concentrations < 10 uM, inhibiting M-CSF and G-CSF-responsive progenitor cells equally. Tyr-MIF did not inhibit the number of colonies responsive to recombinant interleukin 3 (rmIL-3) or recombinant murine granulocyte-macrophage colony stimulating factor (rmGM-CSF), but significantly reduced colony size of GM-CSF responsive colonies. Colony formation by human low density and CD34+ marrow cells in response to G-CSF was also inhibited by Tyr-MIF and was more sensitive to inhibition than murine progenitor cells. Colony formation by single CD34+ cells was also inhibited by Tyr-MIF, indicating an effect directly on progenitor cells. Incubation of marrow cells in liquid culture and removal of Tyr-MIF prior to quantitating progenitor cell proliferation demonstrated that opioid-induced inhibition was reversible. The inhibitory effect of Tyr-MIF was not blocked by naloxone, a mu receptor specific antagonist, or diminished in mu opioid receptor deficient mice. HPLC analysis of cell-free culture medium containing Tyr-MIF showed no presence of the parent peptide after 24 h while progenitor cell inhibitory activity was retained. Analysis of potential degradation products of Tyr-MIF indicated that only H-Gly-NH9 or H-Gly-NH2 containing peptides inhibited colony forming unit (CFU) proliferation. These results indicate that Tyr-MIF is a reversible inhibitor of mature hematopoietic progenitor cell proliferation, and that this effect is most likely mediated by the degradation product H-Gly-NH2. Potential applications including protection of myeloid cells after cytosuppresive therapy are discussed.

Animals↗
PubMed2005

MIF loss impairs Myc-induced lymphomagenesis.

Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the Emu-Myc lymphoma mouse model, we demonstrate that loss of MIF markedly delays the onset of B-cell lymphoma development in vivo. The molecular basis for this MIF-loss-induced phenotype is the perturbed DNA-binding activity of E2F factors and the concomitantly enhanced tumor suppressor activity of the p53 pathway. Accordingly, premalignant MIF-null Emu-Myc B-cells are predisposed to delayed S-phase progression and increased apoptosis. MIF-deficient lymphomas that do arise under these conditions contain frequent ARF deletions and p53 inactivating mutations. Conversely, MIF expression is retained in tumors developed by wild-type Emu-Myc animals, and the presence of one or both MIF alleles is sufficient to accelerate the development of Myc-induced lymphomas. Collectively, these results indicate that MIF promotes Myc-mediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.

Animals↗
PubMed2002

Macrophage migration inhibitory factor (MIF) expression in human glioblastomas correlates with vascular endothelial growth factor (VEGF) expression.

Macrophage migration inhibitory factor (MIF) is a peptide released upon hypothalamo-pituitary stimulation that acts as a potent endogenous antagonist of the glucocorticoid inhibition of acute inflammatory response and subsequent antigen-specific response. MIF also sustains tumour growth as it promotes angiogenesis, overcomes p53-mediated cell growth arrest and inhibits tumour-specific immune responses. Using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry, we studied MIF expression in 35 human glioblastomas and two normal brains. We compared these results with the expression of vascular endothelial growth factor (VEGF), the most potent angiogenic factor in glioblastomas. We detected MIF in normal cortical neurons and glial cells. All glioblastomas were positive for MIF mRNA with expression levels similar to or higher than those of normal brain. MIF immunoreactivity was seen mainly in tumour cells and less frequently in hyperplastic endothelial cells. The expressions of MIF and VEGF mRNA were strongly correlated (P < 0.0001). Our results demonstrate the expression of MIF in human glioblastomas, and indicate a close relationship with VEGF expression. This is of particular interest given the potential modulation of MIF by glucocorticosteroids.

Adult↗
PubMed1999

Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action.

Macrophage migration inhibitory factor (MIF) is an important pro-inflammatory mediator with the unique ability to counter-regulate the inhibitory effects of glucocorticoids on immune cell activation. MIF is released from cells in response to glucocorticoids, certain pro-inflammatory stimuli, and mitogens and acts to regulate glucocorticoid action on the ensuing inflammatory response. To gain insight into the molecular mechanism of MIF action, we have examined the role of MIF in the proliferation and intracellular signaling events of the well characterized, NIH/3T3 fibroblast cell line. Both endogenously secreted and exogenously added MIFs stimulate the proliferation of NIH/3T3 cells, and this response is associated with the activation of the p44/p42 extracellular signal-regulated (ERK) mitogen-activated protein kinases (MAP). The MIF-induced activation of these kinases was sustained for a period of at least 24 h and was dependent upon protein kinase A activity. We further show that MIF regulates cytosolic phospholipase A2 activity via a protein kinase A and ERK dependent pathway and that the glucocorticoid suppression of cytokine-induced cytoplasmic phospholipase A2 activity and arachidonic acid release can be reversed by the addition of recombinant MIF. These studies indicate that the sustained activation of p44/p42 MAP kinase and subsequent arachidonate release by cytoplasmic phospholipase A2 are important features of the immunoregulatory and intracellular signaling events initiated by MIF and provide the first insight into the mechanisms that underlie the pro-proliferative and inflammatory properties of this mediator.

3T3 Cells↗
PubMed2000

Role of macrophage migration inhibitory factor (MIF) in allergic and endotoxin-induced airway inflammation in mice.

Macrophage migration inhibitory factor (MIF) has recently been forwarded as a critical regulator of inflammatory conditions, and it has been hypothesized that MIF may have a role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Hence, we examined effects of MIF immunoneutralization on the development of allergen-induced eosinophilic inflammation as well as on lipopolysaccharide (LPS)-induced neutrophilic inflammation in lungs of mice. Anti-MIF serum validated with respect to MIF neutralizing capacity or normal rabbit serum (NRS) was administered i.p. repeatedly during allergen aerosol exposure of ovalbumin (OVA)-immunized mice in an established model of allergic asthma, or once before instillation of a minimal dose of LPS into the airways of mice, a tentative model of COPD. Anti-MIF treatment did not affect the induced lung tissue eosinophilia or the cellular composition of bronchoalveolar lavage fluid (BALF) in the asthma model. Likewise, anti-MIF treatment did not affect the LPS-induced neutrophilia in lung tissue, BALF, or blood, nor did it reduce BALF levels of tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-1alpha (MIP-1alpha). The present data suggest that MIF is not critically important for allergen-induced eosinophilic, and LPS-induced neutrophilic responses in lungs of mice. These findings do not support a role of MIF inhibition in the treatment of inflammatory respiratory diseases.

Animals↗
PubMed2000

Macrophage migration inhibitory factor (MIF): its essential role in the immune system and cell growth.

Macrophage migration inhibitory factor (MIF) functions as a pleiotropic protein, participating in inflammatory and immune responses. MIF was originally discovered as a lymphokine involved in delayed hypersensitivity and various macrophage functions, including phagocytosis, spreading, and tumoricidal activity. Recently, MIF was reevaluated as a proinflammatory cytokine and pituitary-derived hormone potentiating endotoxemia. This protein is ubiquitously expressed in various organs, such as the brain and kidney. Among cytokines, MIF is unique in terms of its abundant expression and storage within the cytoplasm and, further, for its counteraction against glucocorticoids. MIF has unexpectedly been found to convert D-dopachrome, an enantiomer of naturally occurring L-dopachrome, to 5,6-dihydroxyindole. However, its physiologic significance remains to be elucidated. It was demonstrated that anti-MIF antibodies effectively suppress tumor growth and tumor-associated angiogenesis, suggesting that MIF is involved not only in inflammatory and immune responses but also in tumor cell growth. At present, MIF cannot be clearly categorized as either a cytokine, hormone, or enzyme. This review presents the latest findings on the role of MIF in the immune system and in cell growth, with regard to tumorigenesis and wound repair, and discusses its potential functions in various pathophysiologic states.

Animals↗
PubMed1996

MIF rediscovered: cytokine, pituitary hormone, and glucocorticoid-induced regulator of the immune response.

The protein that has been historically called macrophage migration inhibitory factor (MIF) was one of the first cytokine activities to be discovered and was originally described to be a T lymphocyte product that inhibited the random migration of macrophages. Over the years, additional molecules with MIF "activity" have been described and the precise role of the original MIF "protein" remained enigmatic. Recent studies have led to the discovery of a pituitary mediator that appears to act as the counterregulatory hormone for glucocorticoid action within the immune system. Isolated as a product of murine anterior pituitary cells, this peptide was sequenced and found to be the mouse homolog of MIF. MIF has the unique property of being released from macrophages and T cells in response to physiological concentrations of glucocorticoids. The secretion of MIF is tightly regulated and decreases at high, anti-inflammatory steroid concentrations. Once released, MIF "overrides" or counterregulates the immunosuppressive effects of steroids on immune cell activation and cytokine production. These observations suggest that MIF fills an important gap in our understanding of how the host initiates and controls immunity. Because glucocorticoids are an integral part of the host's global response to infection or tissue invasion, the physiological role of MIF is to act at an inflammatory site or lymph node to counterbalance the profound inhibitory effects of steroids on the immune response.

Animals↗
PubMed1997

The site and time of expression of MIF in frog development.

A ventrally localized melanization-inhibiting factor (MIF) has been suggested to play a role in the expression of dorsal-ventral pigment patterns in amphibia. Here we investigate the onset and localization of MIF appearance in frog development. The expression of MIF was analyzed in the wild-type and gray-eyed mutant (g/g) of Rana japonica by immunoblotting and immunohistochemistry using an anti-MIF neutralizing monoclonal antibody. Western blot analysis revealed that the anti-MIF antibody recognized approximately 51 kDa and approximately 58 kDa bands. The 51 kDa band first appeared at the external gill stage, while 58 kDa band was additionally detected at the hindlimb bud stage. With the use of immunohistochemistry, it was found that the anti-MIF antibody stained the whole epidermis of the embryos at the external gill stage; however, the staining was stronger in lateral and ventral epidermis than in dorsal. Staining with the anti-MIF antibody was observed only in the outer epidermis of the ventral skin, but not in the dorsal skin during and after metamorphosis. The spatial expression of MIF in the wild-type was the same as that in the gray-eyed mutant. The same immunohistochemical result was obtained in the adults of R. nigromaculata. These results suggest that MIF is involved in the formation of the dorsal-ventral pigment pattern.

Animals↗
PubMed1993

Uptake, content, regulation of plasma concentrations, and binding of Tyr-MIF-1 by the adrenals.

The known occurrence of opiates in the adrenals stimulated us to determine whether Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2), an endogenous peptide that can act as an antiopiate, is present in these glands and whether adrenalectomy affects its concentrations in plasma. The presence of Tyr-MIF-1 in the adrenals of the rat was shown by radioimmunoassay (RIA) and high performance liquid chromatography (HPLC). Binding sites for the tetrapeptide also were found in the adrenal. The concentrations and binding of Tyr-MIF-1 were higher in the adrenal medulla than in the adrenal cortex. The adrenals preferentially trapped 125I-Tyr-MIF-1 as compared with 99mTc-albumin after intravenous administration. However, after correction for tissue weight and vascular space, accumulation of 125I-Tyr-MIF-1 by the adrenals was in the general range seen for several other tissues. The concentrations of Tyr-MIF-1-like immunoreactivity determined by RIA in the plasma of adrenalectomized rats were increased in comparison with sham operated or unoperated controls. This approximate doubling was unchanged by the site of sampling: hepatic portal vein, renal vein, inferior vena cava, jugular vein, or truncal blood. Hypophysectomy, removal of the adrenal medulla, or treatment with corticosterone also did not block this increase. Tyr-MIF-1-like immunoreactivity in the plasma of adrenalectomized rats eluted at the same position by HPLC as did the synthetic Tyr-MIF-1 standard. Thus, the adrenal gland contains Tyr-MIF-1 and can affect its concentrations in plasma.

Adrenal Cortex↗