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At least 19 recordsLinked to original sources
PubMed2005

Chaperone-like activity of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor is a ubiquitous multifunctional cytokine having diverse immunological and neuroendocrine properties. Although this protein is known to be released into the circulation from the secretory granules of anterior pituitary or directly from immune cells as a consequence of stress, its participation in heat stress-induced aggregation of proteins has not yet been reported. We provide here the first evidence that the macrophage migration inhibitory factor possesses chaperone-like properties. It was shown to exist in the form of a mixture of low and high molecular weight oligomers. At heat stress temperatures the large oligomers dissociate into monomers that bind and stabilize thermally denatured malate dehydrogenase and glycogen phosphorylase b and thus prevent aggregation of the model proteins. Similar chaperone-like effects were also observed in the presence of partially purified brain extract containing besides the macrophage migration inhibitory factor a number of ubiquitous hydrophobic low molecular weight proteins identified by N-terminal microsequence analysis. Being highly stable and hydrophobic, the macrophage migration inhibitory factor in combination with other proteins of similar properties may comprise a family of constitutively expressed "small chaperones" that counteract the early onset of stress, around physiological conditions, when heat shock proteins are not abundant.

Animals↗
PubMedDate not supplied

Stimulation of vascular smooth muscle cell migration by macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is a well known proinflammatory factor that influences the migration and proliferation of various cell types, predominantly monocytes and macrophages. Recent evidence suggests an important role for MIF in the progression of atherosclerosis and restenosis. For this reason, we studied the effect of MIF on platelet-derived growth factor-BB (PDGF-BB)-induced migration and PDGF receptor protein expression in vascular smooth muscle cells (VSMCs). Furthermore, the possibility of MIF influencing the migration of VSMCs was investigated. Our results show that short-term incubation of MIF is able to enhance PDGF-BB-induced migration. Long-term incubation decreases PDGF-BB-induced migration, but preserves a short-term stimulatory effect. These effects are not regulated at the level of PDGF receptor protein expression. MIF also acts as a chemoattractant for VSMCs, with a maximum response at 15 ng/ml. In contrast, the proliferation of VSMCs was unaffected by MIF. We conclude that MIF has a biphasic effect on VSMC migration. It remains unclear whether this effect is direct or involves the secretion of unidentified promigratory factors. Exogenous MIF does not stimulate VSMC proliferation; however, a role for MIF in proliferation cannot be fully ruled out. In view of the known key contributions of macrophage-derived MIF and VSMCs, the observed effects may well play a role in the progression of atherosclerosis and restenosis.

Animals↗
PubMed2005

Ketone bodies affect the enzymatic activity of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF), a long known proinflammatory cytokine exhibits perplexing enzymatic activities: tautomeric conversion of D-dopachrome and phenylpyruvate. Whether these catalytic activities bear functional relevance regarding MIF's multifaceted roles is under current scrutiny. Nevertheless, intense search has already started for pharmacological agents that target MIF's tautomerase activity. We have probed several antiinflammatory compounds against keto--enol (enolase) and enol--keto (ketonase) conversion of phenylpyruvate by MIF with spectrophotometry. We have identified acidic CH groups as markers of inhibitor potency toward MIF phenylpyruvate tautomerase. Among simple model molecules with strong acidic CH groups we found acetylacetone the best inhibitor particularly against the ketonase activity. Ketones of physiological importance - ketone bodies - also feature acidic CH groups and have been reported to exert certain anti-inflammatory effects. In this paper we report that ketone bodies inhibit preferentially the ketonase activity of MIF in vitro. Future studies should address whether such an interaction might operate in vivo and delineate its possible relevance concerning cytokine and non-cytokine roles of MIF.

Enzyme Inhibitors↗
PubMed2005

Charge heterogeneity of bovine brain macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is known as a ubiquitous pluripotent cytokine originally identified for its capacity to inhibit the random migration of macrophages in vitro. It is recognized as an important regulator of the immunological, neuroendocrine and enzymatic processes. MIF is widely expressed in brain, but its role in the nervous system is not yet understood. In the course of the study of the primary structure of bovine brain MIF we have previously identified a number of MIF-related proteins having identical N-terminal sequences. In this paper we report the results of isoelectric focusing of MIF isolated to a homogeneous state from bovine brain that revealed MIF charge heterogeneity. We have detected isoelectric forms of MIF with pI values of 6.9, 7.0, 7.3, and 7.8. The diverse actions of MIF within the immuno-neuroendocrine system is suggested to be a result of its occurrence in different isoforms and oligomerization states.

Animals↗
PubMed1998

Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is a secreted protein that activates macrophages, neutrophils and T cells, and is implicated in sepsis, adult respiratory distress syndrome and rheumatoid arthritis. The mechanism of MIF function, however, is unknown. The three-dimensional structure of MIF is unlike that of any other cytokine, but bears striking resemblance to three microbial enzymes, two of which possess an N-terminal proline that serves as a catalytic base. Human MIF also possesses an N-terminal proline (Pro-1) that is invariant among all known homologues. Multiple sequence alignment of these MIF homologues reveals additional invariant residues that span the entire polypeptide but are in close proximity to the N-terminal proline in the folded protein. We find that p-hydroxyphenylpyruvate, a catalytic substrate of MIF, binds to the N-terminal region and interacts with Pro-1. Mutation of Pro-1 to a glycine substantially reduces the catalytic and cytokine activity of MIF. We suggest that the underlying biological activity of MIF may be based on an enzymatic reaction. The identification of the active site should facilitate the development of structure-based inhibitors.

Amino Acid Sequence↗
PubMed2003

Macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is a ubiquitous protein that is found in virtually all cells. Its precise function in the majority of cells is not known, but studies performed over the last decade indicate that it is a critical upstream regulator of the innate and acquired immune response. MIF is released under a variety of circumstances, regulates cytokine secretion and the expression of receptors that are involved in innate immunity, inhibits p53 function, and activates components of the mitogen-activated protein kinase and Jun-activation domain-binding protein-1 (Jab-1) pathways. Compelling in vitro and in vivo evidence has focused attention on this protein as a new therapeutic target for inflammatory and autoimmune diseases. Unique structural features, including an intrinsic catalytic activity, offer attractive opportunities for the discovery and design of therapeutic MIF inhibitors.

Animals↗
PubMed2004

[A novel mediator--macrophage migration inhibitory factor].

Macrophage migration inhibitory factor(MIF) was discovered as a soluble factor associated with the mechanism of delayed-type hypersensitivity. At present, MIF is accepted as a multifunctional cytokine involved in a broad-spectrum pathological events relevant to the immune system and tumorigenesis. Following the cloning of human MIF cDNA, novel biological functions of MIF have been demonstrated. For example, MIF is released from the anterior pituitary gland in endotoxin stimuli, and as a proinflammatory cytokine and glucocorticoid-induced immunomodulator produced by a variety of inflammatory stimuli. From these findings, it is conceivable that MIF would be a novel indicator, suggesting systemic inflammatory conditions, such as septicemia. Recently, it was found that Toll-like receptor 4 could be regulated by MIF, suggesting its involvement in the innate immunity.

Animals↗
PubMed2000

Murine monoclonal antibodies directed against human recombinant Macrophage Migration Inhibitory Factor.

Macrophage Migration Inhibitory Factor (MIF) is a crucial component of the immune system acting together with glucocorticosteroids to regulate immunity and inflammation. Understanding of its many putative functions and action mechanisms is still ambiguous. Due to the newest findings that a local MIF expression is up regulated in allograft rejection and in glomerulonephritis, an interest in MIF research is increasing and is focused on possibilities of anti-MIF treatment. In the present work new murine monoclonal antibodies (MAbs) directed against human recombinant MIF (hrMIF) are described. hrMIF protein used for the immunisation was tested for its biological activity and has evident macrophage migration inhibitory activity. The selected MAbs were purified and further characterised. They recognised MIF in a Western blot experiment after a native IEF. Anti-MIF MAb designated as M1 inhibited MIF activity in the test, which was performed in the 48 well Boyden chamber system. It is presumed that M1 MAb could be used as a potential therapeutic agent.

Animals↗
PubMed2002

Macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) has been proposed to be the physiologic counter-regulator of glucocorticoid action within the immune system. In this role, MIF's position within the cytokine cascade is to act in concert with glucocorticoids to control both the "set point" and the magnitude of the inflammatory response. As well as overriding the immunosuppressive effects of glucocorticoids, it is now well established that MIF has a direct proinflammatory role in inflammatory diseases, such as sepsis, rheumatoid arthritis, and glomerulonephritis. The functions of MIF within the immune system are both unique and diverse, and although a unified molecular mechanism of action remains to be elucidated, there have been significant advances in our understanding of how MIF affects cellular processes. This review discusses the pathogenic role of MIF in inflammatory disease and highlights the novel structural, functional, and mechanistic properties of MIF.

Glucocorticoids↗
PubMed2006

Functional characterization of the Plasmodium falciparum and P. berghei homologues of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is a mammalian cytokine that participates in innate and adaptive immune responses. Homologues of mammalian MIF have been discovered in parasite species infecting mammalian hosts (nematodes and malaria parasites), which suggests that the parasites express MIF to modulate the host immune response upon infection. Here we report the first biochemical and genetic characterization of a Plasmodium MIF (PMIF). Like human MIF, histidine-tagged purified recombinant PMIF shows tautomerase and oxidoreductase activities (although the activities are reduced compared to those of histidine-tagged human MIF) and efficiently inhibits AP-1 activity in human embryonic kidney cells. Furthermore, we found that Plasmodium berghei MIF is expressed in both a mammalian host and a mosquito vector and that, in blood stages, it is secreted into the infected erythrocytes and released upon schizont rupture. Mutant P. berghei parasites lacking PMIF were able to complete the entire life cycle and exhibited no significant changes in growth characteristics or virulence features during blood stage infection. However, rodent hosts infected with knockout parasites had significantly higher numbers of circulating reticulocytes. Our results suggest that PMIF is produced by the parasite to influence host immune responses and the course of anemia upon infection.

Amino Acid Sequence↗
PubMed2006

Regulation of IL-1 and TNF receptor expression and function by endogenous macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) has a key role in regulation of innate and adaptive immunity and is implicated in sepsis, tumorigenesis, and autoimmune disease. MIF deficiency or immunoneutralization leads to protection against fatal endotoxic, exotoxic, and infective shock, and anti-inflammatory effects in other experimental models of inflammatory disease. We report a novel regulatory role of MIF in type 1 IL-1R and p55 TNFR expression and function. Compared with wild-type cells, MIF-deficient cells were hyporesponsive to IL-1- and TNF-induced MAPK activity, AP-1 activity, and cellular proliferation, while NF-kappaB function was preserved. Hyporesponsiveness of MIF-deficient cells was associated with down-regulation of cytokine receptor expression, which was restored by reconstitution of either an upstream kinase of MAPK, MAPK/ERK kinase, or MIF. These data suggest that endogenous MIF is required for cytokine activation of MAPK/AP-1 and cytokine receptor expression. This autocrine regulatory pathway defines an important amplifying role of endogenous MIF in cytokine-mediated immune and inflammatory diseases and provides further molecular evidence for the critical role of MIF in cellular activation.

Animals↗
PubMed1997

Insulin secretion is regulated by the glucose-dependent production of islet beta cell macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF), originally identified as a cytokine secreted by T lymphocytes, was found recently to be both a pituitary hormone and a mediator released by immune cells in response to glucocorticoid stimulation. We report here that the insulin-secreting beta cell of the islets of Langerhans expresses MIF and that its production is regulated by glucose in a time- and concentration-dependent manner. MIF and insulin colocalize by immunocytochemistry within the secretory granules of the pancreatic islet beta cells, and once released, MIF appears to regulate insulin release in an autocrine fashion. In perifusion studies performed with isolated rat islets, immunoneutralization of MIF reduced the first and second phase of the glucose-induced insulin secretion response by 39% and 31%, respectively. Conversely, exogenously added recombinant MIF was found to potentiate insulin release. Constitutive expression of MIF antisense RNA in the insulin-secreting INS-1 cell line inhibited MIF protein synthesis and decreased significantly glucose-induced insulin release. MIF is therefore a glucose-dependent, islet cell product that regulates insulin secretion in a positive manner and may play an important role in carbohydrate metabolism.

Animals↗
PubMed1996

Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) was the first cytokine to be described, but for 30 years its role in the immune response remained enigmatic. In recent studies, MIF has been found to be a novel pituitary hormone and the first protein identified to be released from immune cells on glucocorticoid stimulation. Once secreted, MIF counterregulates the immunosuppressive effects of steroids and thus acts as a critical component of the immune system to control both local and systemic immune responses. We report herein the x-ray crystal structure of human MIF to 2.6 angstrom resolution. The protein is a trimer of identical subunits. Each monomer contains two antiparallel alpha-helices that pack against a four-stranded beta-sheet. The monomer has an additional two beta-strands that interact with the beta-sheets of adjacent subunits to form the interface between monomers. The three beta-sheets are arranged to form a barrel containing a solvent-accessible channel that runs through the center of the protein along a molecular 3-fold axis. Electrostatic potential maps reveal that the channel has a positive potential, suggesting that it binds negatively charged molecules. The elucidated structure for MIF is unique among cytokines or hormonal mediators, and suggests that this counterregulator of glucocorticoid action participates in novel ligand-receptor interactions.

Amino Acid Sequence↗
PubMed2001

Regulation of the CTL response by macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) has been shown to be a pivotal cytokine that mediates host inflammatory and immune responses. Recently, immunoneutralization of MIF has been found to inhibit tumor growth in mice; however, the contributing mechanisms underlying this effect have not been well defined. We investigated whether MIF plays a regulatory role in the expression of CTL activity. In a mouse model of the CTL response using the OVA-transfected tumor cell line EL4 (EG.7), we found that cultures of splenocytes obtained from EG.7-primed mice secrete high levels of MIF following Ag stimulation in vitro. Notably, parallel splenocyte cultures treated with neutralizing anti-MIF mAb showed a significant increase in the CTL response directed against EG.7 cells compared with control mAb-treated cultures. This effect was accompanied by elevated expression of IFN-gamma. Histological examination of the EG. 7 tumors from anti-MIF-treated animals showed a prominent increase in both CD4(+) and CD8(+) T cells as well as apoptotic tumor cells, consistent with the observed augmentation of CTL activity in vivo by anti-MIF. This increased CTL activity was associated with enhanced expression of the common gamma(c)-chain of the IL-2R that mediates CD8(+) T cell survival. Finally, CD8(+) T lymphocytes obtained from the spleens of anti-MIF-treated EG.7 tumor-bearing mice, when transferred into recipient tumor-bearing mice, showed increased accumulation in the tumor tissue. These data provide the first evidence of an important role for MIF in the regulation and trafficking of anti-tumor T lymphocytes in vivo.

Adjuvants, Immunologic↗
PubMed1999

A kinetic and stereochemical investigation of the role of lysine-32 in the phenylpyruvate tautomerase activity catalyzed by macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF), an immunoregulatory protein, exhibits a phenylpyruvate tautomerase (PPT) activity. The catalytic mechanism of this activity has recently attracted attention in an effort to determine whether there is a relationship between the PPT activity and the role of MIF in various immune and inflammatory processes. One of the active site residues is lysine-32, which is postulated to play two roles: it assists in substrate binding through an interaction with a carboxylate oxygen at C-1 of phenylpyruvate, and it may be partially responsible for lowering the pK(a) of the catalytic base, Pro-1. The role of Lys-32 has been investigated by changing it to an alanine and an arginine and determining the kinetic parameters, the stereoselectivity, the competitive inhibition, and the pH dependence of the resulting K32A- and K32R-catalyzed reactions. For the K32R mutant, these properties are mostly comparable to those determined for the wild type with two exceptions. There is a modest decrease in the stereoselectivity of the reaction and in the binding affinity of the competitive inhibitor, (E)-2-fluoro-p-hydroxycinnamate. These differences are likely due to the increased steric bulk of arginine. For the K32A mutant, there are 11- and 12-fold decreases in k(cat) and k(cat)/K(m), respectively, using phenylenolpyruvate. Part of the decrease in activity can be attributed to the observed increase of 1. 3 units in the pK(a) of Pro-1. It was also found that the loss of the electrostatic interaction did not significantly affect the stereoselectivity of the K32A-catalyzed reaction, although it did result in a decrease in the binding affinity of the competitive inhibitor. The combination of these results indicates that the primary function of Lys-32 in the PPT activity of MIF is to lower the pK(a) of Pro-1. The interactions responsible for the stereoselectivity of the PPT activity were further delineated by examining the wild type- and K32A-catalyzed reactions with an alternate substrate, 2-hydroxy-2,4-pentadienoate, in which the phenyl group of phenylenolpyruvate is replaced with a double bond. The effect of this substitution is moderate as evidenced by the observation that the ketonization of 2-hydroxy-2,4-pentadienoate by the wild type protein is more stereoselective than the K32R-catalyzed ketonization of phenylenolpyruvate but not as stereoselective as the K32A-catalyzed ketonization of phenylenolpyruvate. However, the low degree of stereoselectivity observed for the K32A-catalyzed reaction indicates that an electrostatic interaction between the protein and 2-hydroxy-2, 4-pentadienoate is now crucial.

Animals↗
PubMed2002

Macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) has been proposed to be the physiologic counter-regulator of glucocorticoid action within the immune system. In this role, MIF's position within the cytokine cascade is to act in concert with glucocorticoids to control both the "set point" and the magnitude of the inflammatory response. As well as overriding the immunosuppressive effects of glucocorticoids, it is now well established that MIF has a direct proinflammatory role in inflammatory diseases, such as sepsis, rheumatoid arthritis, and glomerulonephritis. The functions of MIF within the immune system are both unique and diverse, and although a unified molecular mechanism of action remains to be elucidated, there have been significant advances in our understanding of how MIF affects cellular processes. This review discusses the pathogenic role of MIF in inflammatory disease and highlights the novel structural, functional, and mechanistic properties of MIF.

Journal Article↗
PubMed1980

Chemical characterization of macrophage cytotoxicity factor, macrophage migration inhibitory factor, T-helper cell-replacing factor and colony-stimulating factor from culture supernatants of concanavalin A-stimulated murine spleen cells.

Supernatants from Concanavalin A-stimulated murine spleen cells were subjected to hydrophobic interaction chromatography on phenyl-Sepharose. Macrophage cytotoxicity factor (MCF), macrophage migration inhibitory factor (MIF), T-helper cell-replacing factor (TRF) and colony-stimulating factor (CSF) were bound at high ionic strength and were released stepwise at low ionic strength. CSF thus could be separated from MCF, MIF and TRF and the bulk of other proteins. Chromatograhy of pools containing MCF, MIF and TRF on Sephadex did not lead to a separation of the three activities which were all found in a molecular weight range of 25.000-55.000. Isoelectric focusing of these pools in pH range from 4 to 9 gave two peaks for MCF in a single sharp peak at pH 5.3. The results demonstrate that the four biological activities can be distinguished on a chemical basis and are accessible for purification and chemical characterization.

Animals↗
PubMed1998

Effects of macrophage migration inhibitory factor and macrophage migration stimulatory factor on function and survival of foetal dopaminergic grafts in the 6-hydroxydopamine rat model of Parkinson's disease.

Activated microglia play an important role in the rejection of intracerebral grafts and the degeneration of axotomized neurones. We studied the effect of macrophage migration stimulatory factor (MSF) or macrophage migration inhibitory factor (MIF) on allogeneic foetal mesencephalic dopaminergic grafts transplanted into the striatum of 6-hydroxydopamine-lesioned rats. Rotation testing revealed a significant compensation of lesion-induced motor asymmetry 3 weeks post-grafting in animals treated with MIF and vehicle-treated controls compared with pre-graft values (Student's t-test, P < or = 0.005) and MSF-treated animals (ANOVA, post hoc Fisher PLSD test, P < or = 0.05). The MSF group showed no significant compensation. Graft recipients with MIF application (1452.06 +/- 164.32 tyrosine hydroxylase-positive ventral mesencephalic cells) and controls (1753.21 +/- 165.51 tyrosine hydroxylase-positive neurones) displayed good graft survival. Animals with MSF application showed a significant reduction of tyrosine hydroxylase-positive grafted cells (MSF 570.36 +/- 209.49 cells) and graft volumes compared with the MIF and the control group (ANOVA, post hoc Fisher PLSD test, P < or = 0.05). The proportional area of microglia was significantly reduced in MIF animals compared with control animals (ANOVA, post hoc Fisher PLSD test, P < or = 0.001). Activated microglia and macrophages were reduced by half in the MIF-treated group compared with MSF animals and controls. We conclude that intrastriatal injections of MSF result in impaired function and survival of allogeneic ventral mesencephalon (VM) grafts 3 weeks after transplantation. MIF can reduce the number of microglia and macrophages in allogeneic foetal VM grafts. A reduction of microglia via MIF application did not enhance graft function and survival.

Animals↗