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Neuroendocrine properties of macrophage migration inhibitory factor (MIF).

The cytokine macrophage migration inhibitory factor (MIF) is produced by neuroendocrine and immune tissues and possesses several features that allow it to be characterized as a neuroendocrine mediator. Its pro-inflammatory action and its pathogenic role in inflammatory diseases, such as septic shock, arthritis and other diseases, have clearly been demonstrated and may be based in part on neuroendocrine mechanisms. Macrophage migration inhibitory factor possesses glucocorticoid-antagonist properties within the immune system and participates in the regulation of several endocrine circuits. This review summarizes the current state of MIF research and focuses on MIF expression and function in nervous and endocrine tissues.

Animals↗

HIF1alpha delays premature senescence through the activation of MIF.

Premature senescence in vitro has been attributed to oxidative stress leading to a DNA damage response. In the absence of oxidative damage that occurs at atmospheric oxygen levels, proliferation of untransformed cells continues for extended periods of time. We have investigated the role of the hypoxia-inducible factor 1alpha (HIF1alpha) transcription factor in preventing senescence in aerobic and hypoxic conditions. Using embryonic fibroblasts from a conditional HIF1alpha knockout mouse, we found that loss of HIF1alpha under aerobic conditions significantly accelerated the onset of cellular senescence, and decreased proliferation under hypoxia. Furthermore, we identify the macrophage migration inhibitory factor (MIF) as a crucial effector of HIF1alpha that delays senescence. Inhibition of MIF phenocopies loss of HIF1alpha. Our findings highlight a novel role for HIF1alpha under aerobic conditions, and identify MIF as a target responsible for this function.

Aerobiosis↗

Macrophage inhibitor factor (MIF) in cutaneous lymphoproliferative diseases.

Macrophage migration inhibitor factor (MIF) activity in the sera of patients with mycosis fungoides, Sézary syndrome, and cutaneous lymphoma was observed in the sera of eight of the ten patients with stage II (infiltrative) mycosis fungoides, but in only one of the eight patients with stage I and in neither of the two patients with stage III mycosis fungoides. Two of the three patients with Sézary syndrome had MIF in the serum. No MIF was observed in cutaneous lymphoma. These data support the concept that Sézary syndrome and mycosis fungoides are T-cell diseases, and transitional, prelymphomatous diseases.

Cell Migration Inhibition↗

Evidence for presence of Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) in human brain cortex.

Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) was previously isolated from bovine hypothalamus. We have now purified it from the parietal cortex of human brain tissue by gel filtration chromatography and four subsequent high performance liquid chromatographic steps. During isolation, the peptide content was followed by radioimmunoassay and compared with the elution of synthetic Tyr-MIF-1 in identical chromatographic systems. This extends evidence for the presence of Tyr-MIF-1 from bovine to human brain tissue and from hypothalamus to cortex.

Amino Acid Sequence↗

Conformational studies of N-Tyr-MIF-1 in aqueous solution by 1H nuclear magnetic resonance spectroscopy.

N-Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) is an endogenous brain peptide with multiple effects on animal behavior. However, there have been no studies on the conformation of this tetrapeptide. In this report, we studied the conformation of N-Tyr-MIF-1 in aqueous solution by conventional one-dimensional and two-dimensional (COSY and NOESY) 1H nuclear magnetic resonance spectroscopy at 300 MHz. A complete set of assignments for the resolved resonances and approximate assignments for the overlapping resonances were made. The results demonstrate that N-Tyr-MIF-1 is in slow exchange between two conformers, most likely determined by the cis and trans states of the proline residue. The minor conformation represents 30 +/- 3% of the population over the temperature range from 3 degrees to 73 degrees. In the major conformation, the tyrosine aromatic ring appears to be close enough to interact directly with the proline pyrrolidine ring, as indicated by a strong temperature dependence of the proline C beta H, C delta H and C delta H' chemical shifts. In contrast, this interaction of the tyrosine and proline rings is not present in the minor conformation.

Amino Acid Sequence↗

A diversified family of 12-kDa proteins with a high amino acid sequence similarity to macrophage migration-inhibitory factor (MIF).

Two isoforms of a bovine-brain-derived 12-kDa protein (designated p12a and p12b) whose N-termini have a high amino acid sequence similarity with the glycosylation-inhibiting factor (GIF) and macrophage migration-inhibitory factor (MIF) were purified to homogeneity. The complete amino acid sequence of bovine p12a (pI 9.5) was determined by Edman degradation of the intact molecule and overlapping fragments generated by proteolytic cleavage. The p12a isoform has nine and ten conservative substitutions versus human GIF (hGIF) and human MIF (hMIF), respectively. Molecular filtration revealed that both isoforms of p12 exist as monomers in aqueous solution. Circular dichroism spectra indicate that both isoforms of p12 consist of 39 +/- 3% alpha helix, 23 +/- 3% beta structure and 15 +/- 3% beta turns. Although the N-terminal parts of p12a and p12b have weak amino acid sequence similarity with that of glutathione S-transferase (GST) neither isoform of p12 was bound to a GST-affinity gel nor had GST activity. Despite a high amino acid sequence similarity with human MIF neither of the p12 isoforms inhibited migration of the mouse monocyte-macrophage cells P338D1.

Amino Acid Sequence↗

Tyr-MIF-1 attenuates antinociceptive responses induced by three models of stress-analgesia.

Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2), a biologically active brain peptide, has previously been shown to antagonize the analgesia induced by morphine. In this report experiments are described in which mice were tested on the hot-plate in three models of antinociception - shock, novel environment, and warm-water swim - after the administration of various doses of Tyr-MIF-1 without any exogenous opiates. The peptide reduced the antinociception produced by all three methods of inducing endogenous antinociception. These results add further support for the existence of peptides like Tyr-MIF-1 that act as opiate antagonists.

Analgesia↗

Potentiation of MIF production by lymphocytes of Trichinella spiralis-infected mice.

In order to further investigate the mechanism involved in the immunopotentiation following Trichinella spiralis infection, mice were injected intraperitoneally with either heat-killed or viable bacillus Calmette-Guérin (BCG) 28 days after oral infection with 200 nematode larvae. Delayed-type hypersensitivity (DTH) was assessed 28 days later by measuring levels of migration inhibitor factor (MIF) elicited by Old Tuberculin challenge. Sensitization with killed BCG produced only negligible amounts of MIF; however, prior T. spiralis infection resulted in significantly increased titers of MIF, reaching levels induced by viable BCG. The data indicated that a lymphokine component may be involved in addition to non-specific mechanisms previously proposed.

Animals↗

Effects of newly synthesized analogs of MIF-1 containing unnatural amino acids on electrically evoked smooth muscle contractions.

New MIF-1 (Pro-Leu-Gly-NH2) analogs containing unnatural amino acids such as L-canavanine (Cav) and L-cysteic acid S-(2-aminoethyl)amide (sLys) have been synthesized and in vitro experiments were performed to study their action on neurotransmission in target tissues with adrenergic and cholinergic neurotransmission. The experiments were carried out on electrically stimulated proximal guinea pig ileum (GPI) and the prostatic part of rat and rabbit vasa deferentia (VDR, VDRabb). The present results show that the newly synthesized Cav2-MIF and sLys2-MIF might affect electrically evoked smooth muscle contractions.

Adrenergic Agents↗

Production of MIF-like supernatants by rheumatoid arthritis lymphocytes stimulated by immunoglobulin G.

Patients with rheumatoid arthritis (RA), patients with positive tuberculin (PPD) skin-tests and controls were studied. The lymphocytes from these groups were cultured in serum-free medium to obtain cell-free supernatants. These lymphocyte cultures were pre-incubated with the appropriate antigen or reconstituted after removal of the cells. Supernatants from RA lymphocytes stimulated in vitro by IgG induced an inhibition of the leucocyte migration, as well as the supernatants from tuberculin-sensitized lymphocytes. However, supernatants from non-RA lymphocytes or tuberculin-unsensitized lymphocytes did not show such an inhibition. These MIF-like supernatants have been studied by Sephadex G-100 gel filtration. A MIF activity has been found for PPD and IgG supernatants between the chymotrypsinogen (MW 23,000) and the lysozyme (MW 17,000). This seems to agree with the classical region where MIF can be usually isolated.

Arthritis, Rheumatoid↗

[Frequency of amebiasis and other intestinal protozoal diseases. An epidemiological study with the aid of MIF technic].

Advantages and disadvantages of various laboratory techniques used for the diagnosis of intestinal protozoa are discussed. The importance of a correct parasitological diagnosis is emphasized. The MIF procedure has been investigated with regard to its reliability and found to be very effective due to its high diagnostic yield and reproducibility in repeated examinations. The incidence rates found in our material agreed well with those in the literature, thus enhancing the value of the MIF procedure. The feces of 1005 persons returning from the tropics during the first 8 months of 1975 have been examined by the MIF technique and assessed for intestinal protozoa. Apathogenic amebae were found four times as often as E. histolytica. The incidence was 52.7/1000 for E. histolytica and 70.6/1000 for Giardia lamblia. Multiple parasitosis is often diagnosed. E. histolytica is very likely to be encountered when two or three apathogenic amebae are present.

Eukaryota↗

[An experimental study on the contents of enkephalins in the cerebrospinal fluid in rabbits with unilateral destructive lesions produced in the substantia nigra and their relation to the regulation of MIF-1].

The changes of the contents of enkephalins in cerebrospinal fluid (CSF) and the action of MIF-1 in rabbit experimental models of Parkinson's disease were studied. In the experiment, the rabbits received injection of 6-hydroxydopamine (6-OH DA) into the unilateral substantia nigra. The contents of Met-enkephalin (MEK) and Leuenkephalin (LEK) in the CSF of the fourth ventricles of the normal control rabbits and those with destructive lesions in the substantia nigra were determined with radio-immunoassay. The concentrations of MEK and LEK in CSF of the rabbit models increased markedly to 14.3 and 28.2 folds in the controls respectively. The increased enkephalin content in CSF could be reduced to the normal level by intravenous administration of MIF-I. The results indicated that the action of MIF-I may be one of the important factors in alleviating the symptoms of parkinsonian patients.

Animals↗

Suppression of B cell MIF production by T cells and soluble T cell-derived factors.

Purified populations of guinea pig B cells from nonimmunized animals may be stimualted by PPD or LPS to produce MIF. Unfractionated lymphocyte suspensions from these animals do not produce MIF under these conditions. Reconstitution of B cells with T cells abolishes their ability to generate detectable MIF. A soluble factor obtained from stimulated T cell cultures (MIFIF) is also capable of suppressing this B cell activity. Thus suppressor T cells can interfere with lymphokine production by B cells and this effect is mediated at least in part by a soluble factor. This previously undescribed capacity of T cells may provide an explanation for the fact that B cells do not appear to play a role in reactions of cell-mediated immunity in vivo.

Animals↗

Effects of the tripeptides TRH, MIF and MAF on the cerebral dopaminergic system.

Some central effects of the tripeptides TRH (thyroliberine), MIF (melanostatine or C-terminal fragment of oxytocine) and MAF (C-terminal fragment of gastrine) have been studied in experiments on mice and rats. Upon intraperitoneal administration in mice, TRH and MIF exercise central stimulating effects: they reverse the reserpine-induced decrease in the rectal temperature, ptosis of the eyelids, hypomotility, decreased content of the cerebral homovanillic acid (HVA); they antagonize haloperidol catalepsy and the increased HVA concentration). The tripeptides potentiate apomorphine stereotypy in rats, when injected in the striatum. The results obtained characterize TRH and MIF as drugs which are capable of activating the cerebral dopaminergic receptors by antagonizing the effects of reserpine and haloperidol, MAF--as a substance acting similar to the dopaminergic receptor blockers. Consequently, the cerebral dopaminergic system is an important unit for the realization of the central effects of these low-molecular peptides.

Animals↗

[Idiotype-specific inactivation by xenogeneic antisera of T killers but not of T-MIF producers immune to H-2 complex antigens].

Following appropriate absorption rabbit serum to CBA anti-C57BL/6 lymph node cells (rabbit ISS) and rat serum to enriched CBA anti-C57BL/6 T killers (rat ISS) selectively inhibited the activity of K-anti-b T killers but did not affect T killers of other specificities (K-anti-d, d-anti-b). Rabbit ISS did not suppress the capacity of CBA anti-C57BL/6 (K-anti-b) T cells to produce MIF. Under the same conditions, anti-Thy-1.2 serum inactivated killers and K-anti-b MIF-producers. The findings indicate that the killers and MIF-producers immune to the antigens of H-2 complex constitute different subpopulations of T cells, which appear to carry nonidentical sets of idiotypes.

Animals↗

Production of migration inhibition factor (MIF) by purified human T cell subpopulations.

T cells possessing suppressor activity (TG) were isolated from normal human peripheral blood by rosetting with IgG-coated ox red blood cells (OxRBC) as shown by their ability to inhibit pokeweed mitogen (PWM) induced proliferation and Ig synthesis in vitro. The suppressor activity of the intact T cell and Tg cell fractions was enhanced by concanavalin A (Con A) stimulation for 48 hr and supernatants from these Con A-treated cell cultures, after removal of mitogen, contained migration inhibition factor (MIF). Its release appeared to be primarily a function of the TG cells. The bulk of the MIF activity was present in a gel filtration fraction of mol. wt approx. 25,000, similar to that found in previous studies of Con A- or antigen-induced MIF in man.

Cell Differentiation↗

Histamine-induced suppressor factor (HSF): effect on migration inhibitory factor (MIF) production and proliferation.

Histamine added in vitro to cultures of sensitized lymphocytes suppresses antigen-induced production of migration inhibitory factor (MIF) and proliferation by these cells. Recent studies have suggested that lymphocytes bearing histamine type-2 receptors play a regulatory role in these in vitro responses. The present studies were undertaken to determine if suppressor function by cells having histamine receptors was mediated through a soluble product. It was found that lymph node cells from nonimmune or immune strain 2 guinea pigs elaborate a nondialyzable factor into the culture supernatant when incubated with 10(-3) to 10(-5) M histamine (histamine-induced suppressor factor of HSF). HSF, when cocultured with sensitized lymphocytes, suppressed their MIF and proliferative responses to antigen. HSF was made by lymphocytes but not macrophages. Its production could be blocked by an H2 receptor antagonist (burimamide) but not an H1 receptor antagonist (chlorpheniramine). Furthermore, the inhibitory effect of HSF was reversible as lymphocytes washed free of the factor after 24 hr and recultured with fresh medium and antigen were able to produce MIF. Gel filtration by Sephadex G-100 chromatography indicated that HSF had an approximate m.w. of 23,000 to 40,000. These results suggest that the release of histamine at the sites of immediate hypersensitivity reactions, possibly by generating HSF activity, may play a regulatory role in the subsequent development of cellular-immune reactions at the same site.

Animals↗

Ly phenotype of lymphocytes producing murine migration inhibitory factor (MIF).

Murine lymphocytes from lymph nodes or peritoneal exudates were tested after treatment with various anti-Ly sera plus complement for their ability to produce MIF in response to stimulation with either antigen or mitogen. When remaining cells in the LN and PEC were stimulated with either Con A or PPD, respectively, it was found that cells of the Lyl set were primarily responsible for MIF production by T cells. This does not rule out the possibility that, under certain circumstances, other T cell sets may produce MIF or material with similar properties after stimulation by antigen.

Animals↗