Macrophage migration inhibitory factor and the discovery of tautomerase inhibitors. (2002 Jun)
macrophage migration inhibitory factor and the discovery of tautomerase inhibitors . macrophage migration inhibitory factor ( MIF ) is a pro inflammatory cytokine released from T cells and macrophages , and is a key molecule in inflammation . although a detailed understanding of the biological functions of MIF has not yet been found , it is known that MIF catalyzes the tautomerization of phenylpyruvate and a non physiological molecule , D dopachrome . A potent tautomerase inhibitor would be expected , as a validation tool , to shed light on role of MIF activity and the relationship between its biological and enzymatic activity . Such tautomerase inhibitors would be useful in the treatment of MIF related diseases , such as sepsis , acute respiratory distress syndrome ( ARDS ) , asthma , atopic dermatitis , rheumatoid arthritis ( RA ) , nephropathy and tumors . In this review , we have focused on ( 1 ) the biological and enzymatic activities of MIF , ( 2 ) the discovery of novel , drug like tautomerase inhibitors of MIF using a structure based computer assisted search , and ( 3 ) a crystallographic and molecular modeling study of the MIF tautomerase inhibitor complexes ( A review with 133 references ) .

Quantitation of macrophage migration inhibitory factor ( MIF ) using the one step sandwich enzyme immunosorbent assay : elevated serum … (2000 Mar)
quantitation of macrophage migration inhibitory factor ( MIF ) using the one step sandwich enzyme immunosorbent assay : elevated serum MIF concentrations in patients with autoimmune diseases and identification of MIF in erythrocytes . We raised monoclonal antibodies against human macrophage migration inhibitory factor ( MIF ) , and developed a one step sandwich enzyme linked immunosorbent assay ( elisa ) method highly specific for human MIF . The elisa system utilizes a solid phase monoclonal antibody as a capture antibody and a horseradish peroxidase conjugated monoclonal antibody as a detector antibody . We used this elisa method to evaluate the serum level of MIF in 240 healthy volunteers ( 140 males and 100 females ) . We found no significant difference in MIF concentration with respect to age . A significant difference was found with respect to sex , with the mean value ( / SD ) for male subjects of 5 . 3 / 2 . 3 , and that for female subjects of 4 . 6 / 2 . 3 ng / ml ( p 0 . 05 ) . We next measured the serum MIF contents of patients with autoimmune diseases , and found that MIF levels were significantly elevated in patients with systemic lupus erythematosus and rheumatoid arthritis , 20 . 0 / 11 . 0 ng / ml and 21 . 7 / 11 . 2 ng / ml , respectively . using anti MIF antibody immobilized sepharose column chromatography , we discovered for …

Macrophage migration inhibitory factor is involved in the pathogenesis of collagen type II induced arthritis in mice. (1997 Jun)
macrophage migration inhibitory factor is involved in the pathogenesis of collagen type II induced arthritis in mice . To determine the importance of macrophage migration inhibitory factor ( MIF ) in the development of arthritis we used an experimental model for rheumatoid arthritis , collagen type II ( CII ) induced arthritis in mice . treatment with neutralizing anti MIF Abs before immunization of ( B10 . Q x DBA / 1 ) F1 with CII led to delayed onset and lowered frequency of arthritis . This was associated with lower levels of igg2a to CII in MIF depleted mice . The proliferative response to CII was stronger in the anti MIF treated mice , whereas no significant effects were seen on Ag induced IFN gamma production in response to CII or on the total serum Ab levels in response to CII . these results provide the first experimental evidence of a role for MIF in the pathogenesis of autoimmune disease .

Glucocorticoids suppress macrophage migration inhibitory factor ( MIF ) expression in a cell type specific manner. (2005 Apr)
glucocorticoids suppress macrophage migration inhibitory factor ( MIF ) expression in a cell type specific manner . MIF is a potent proinflammatory cytokine involved in inflammatory arthritis . glucocorticoids ( GC ) have been reported to induce secretion of MIF in rodent cells , and as MIF counteracts the anti inflammatory effects of GC , this has implications for human inflammatory disease . transient transfection studies showed that the MIF promoter was repressed by dexamethasone ( Dex ) ( 10 nM ) in CEM C7A cells , with up to 50 suppression by 100 nM . however , there was no regulation of the promoter by GC in A549 cells . We also found that subnanomolar concentrations of Dex suppressed MIF secretion , measured by elisa , by 80 in both human T lymphoblasts ( CEM C7A ) and human lung epithelial cells ( A549 ) . endogenous MIF mRNA was also repressed by GC in CEM C7A cells , measured both by northern blot and quantitative RT PCR assays , but there was no such regulation in A549 cells . This suggests that GC affects translation rather than transcription of MIF in A549 cells . these results contradict earlier results with the rat cell line RAW 264 . 7 . therefore , we analysed MIF secretion from RAW 264 . 7 cells but found no GC effect on secretion . understanding how GC regulates MIF in a cell type dependent manner may give insights into GC refractory human inflammatory …

Detection of sarcolectin specific receptors like the cytokine macrophage migration inhibitory factor in rheumatoid nodules. (1999 Oct)
detection of sarcolectin specific receptors like the cytokine macrophage migration inhibitory factor in rheumatoid nodules . The objective of this study was the evaluation of the relation between the N acetyl neuraminic acid binding endogenous lectin sarcolectin and the cytokine macrophage migration inhibitory factor ( MIF ) during development of rheumatoid nodules ( RN ) in seropositive rheumatoid arthritis ( RA ) . sarcolectin was purified and biotinylated . The binding patterns of this probe were analyzed in RN from patients with RA ( n 23 ) and compared with the distribution of antibodies with specificity for MIF , fibrin , fibronectin . In early RN , all areas of the inflammatory tissue displayed presence of receptors for sarcolectin . macrophages were especially positive . In mature rheumatoid nodules binding of sarcolectin was restricted to the periphery of necrotic areas , to endothelial cells and perivascular connective tissue of marginal zones . distribution patterns of MIF were similar but not identical . The histological staining characteristics demonstrate sarcolectin binding receptors in RN that are altered upon disease progression . The finding suggests that specific interactions between this endogenous lectin and MIF may be involved in the course of RA .

Macrophage migration inhibitory factor polymorphisms do not predict therapeutic response to glucocorticoids or to tumour necrosis factor alpha neutralising treatments … (2007 Oct)
macrophage migration inhibitory factor polymorphisms do not predict therapeutic response to glucocorticoids or to tumour necrosis factor alpha neutralising treatments in rheumatoid arthritis . background : macrophage migration inhibitory factor ( MIF ) is an inflammatory mediator associated with RA severity . In various diseases , MIF polymorphisms are associated with clinical response glucocorticoid ( GC ) treatment . It is unclear whether MIF polymorphisms determine GC response in rheumatoid arthritis ( RA ) and to other RA treatments . therefore , the question of whether two functional variants in MIF are associated with the response to tumour necrosis factor ( TNF ) alpha neutralising and GC treatments in RA was investigated . methods : Data from two cohorts of an RA registry were used . For patients who started with tnfalpha neutralising ( infliximab ) or GC treatment , courses with a duration of at least 3 months were included and response to tnfalpha blockers or GC was calculated according to the european league against rheumatism response criteria . MIF 173G C genotyping was achieved using an assay on demand allelic discrimination assay , and alleles of the CATT repeat element were identified using a fluorescently labelled PCR primer and capillary electrophoresis . logistic regression modelling was used for the statistical analysis . results : In total , 192 courses of oral prednisone or methylprednisolone injections in 98 patients with RA and 90 patients with RA who were on tnfalpha neutralising treatments were documented . In all , 27 …

Macrophage migration inhibitory factor and glucocorticoid sensitivity. (2006 Jul)
macrophage migration inhibitory factor and glucocorticoid sensitivity . glucocorticoids ( GCs ) are widely used in the treatment of inflammatory diseases including rheumatoid arthritis ( RA ) . treatment with GC is associated with significant dose dependent side effects . The pro inflammatory cytokine macrophage migration inhibitory factor ( MIF ) has emerged in recent years as a candidate factor which could regulate GC sensitivity . MIF is induced by GC , and is able to override anti inflammatory actions of GCs . In this review , we summarize the pro inflammatory actions of MIF with respect to RA , describe the interactions between MIF and GC and examine new evidence , which identifies MIF as a specific target for steroid sparing .

Macrophage migration inhibitory factor in rheumatoid arthritis. (2005 Apr)
macrophage migration inhibitory factor in rheumatoid arthritis . rheumatoid arthritis is characterised by the interaction of multiple mediators , among the most important of which are cytokines . In recent years , extensive data demonstrates a pivotal role for one cytokine , macrophage migration inhibitory factor ( MIF ) , in fundamental events in innate and adaptive immunity . MIF has now been demonstrated to be involved in the pathogenesis of many diseases , but in the case of RA the evidence for a role of MIF is very strong . MIF is abundantly expressed in the serum of RA patients , and in RA synovial tissue where it correlates with disease activity . MIF induces synoviocyte expression of key proinflammatory genes including TNF , IL 1 , IL 6 , IL 8 , cpla2 , COX2 and MMPs . MIF also regulates the function of endothelial cells and B cells . moreover , MIF is implicated in the control of synoviocyte proliferation and apoptosis via direct effects on the expression of the tumor suppressor protein p53 . In multiple rat and mouse models of RA , anti MIF antibodies or genetic MIF deficiency are associated with significant inhibition of disease . MIF / mice further demonstrate increases in synovial apoptosis . That the human Mif gene is encoded by different functional alleles in subjects with inflammatory disease also provides evidence for the role of MIF in RA . The mechanism of action of MIF is becoming better understood . …

Macrophage migration inhibitory factor and its role in autoimmune diseases. (2004 Dec)
macrophage migration inhibitory factor and its role in autoimmune diseases . after several decades of research into the macrophage migration inhibitory factor ( MIF ) , its diverse actions in the immune system are yet to be fully revealed . What has become clear is that MIF plays an important role in both innate and adaptive immunity . however , while several pathways mediating the function of MIF in the immune system have been established , its role in pathogenic states such as autoimmune diseases has remained unresolved . MIF has been implicated in different autoimmune diseases , including rheumatoid arthritis , glomerulonephritis , and multiple sclerosis , but knowledge about the underlying cellular and molecular mechanisms is just emerging . however , overall it appears that the inhibition of its proinflammatory action is likely to be a successful new therapeutic strategy for some autoimmune diseases , possibly by reducing the need for steroids . As more aspects of the role of this cytokine in the pathogenesis of autoimmune diseases are elucidated , better strategies to target it therapeutically can be expected .

Macrophage migration inhibitory factor in patients with juvenile idiopathic arthritis. (2002 Jan)
macrophage migration inhibitory factor in patients with juvenile idiopathic arthritis . objective : To evaluate serum and synovial fluid ( SF ) levels of macrophage migration inhibitory factor ( MIF ) and in vitro MIF production by peripheral blood mononuclear cells ( pbmcs ) in patients with juvenile idiopathic arthritis ( JIA ) . methods : serum , SF , and culture supernatant levels of MIF were measured by enzyme linked immunosorbent assay . production of MIF by pbmcs was investigated by culturing pbmcs in the absence or presence of 2 different concentrations of concanavalin A . results : serum MIF levels were increased in patients with JIA , and the highest levels were present in patients with systemic onset JIA . In systemic onset JIA , serum levels of MIF correlated with the persistence of systemic features and the number of active joints . pbmcs from patients with systemic onset JIA , when cultured under unstimulated conditions or at suboptimal stimulation , released higher amounts of MIF compared with those from patients with oligoarticular onset JIA or healthy controls . MIF levels in the SF of patients with systemic onset JIA were significantly higher than those in patients with oligoarticular onset JIA . In individual joints , in both systemic onset JIA and oligoarticular onset JIA , SF MIF levels were inversely correlated with the duration of the clinical remission induced by intraarticular administration of triamcinolone hexacetonide . conclusion : MIF appears to be a relevant cytokine in the …

Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor. (2005 Oct)
correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor . objective : To study whether genetic variants of macrophage migration inhibitory factor ( MIF ) , the MIF 173G C and CATT ( 5 8 ) alleles , are associated with disease severity and levels of circulating MIF in patients with rheumatoid arthritis ( RA ) . methods : genotyping was performed in patients with early RA and in healthy controls . demographic data , disease activity , and outcome measurements were compared between patients with and without the MIF variants . MIF 173G C and CATT ( 5 8 ) polymorphisms were genotyped , and a newly developed enzyme linked immunosorbent assay for human MIF was used . allele and genotype distributions of the MIF 173G C and CATT ( 5 8 ) polymorphisms were compared between patients and controls by chi square test . multiple regression analysis was performed to assess the independence of the MIF functional genetic variants as risk factors for radiologic joint damage . results : genotyping of the 173G C and CATT ( 5 8 ) polymorphisms of MIF in RA patients and healthy individuals ( n 277 each ) revealed similar frequencies of genotypes and haplotypes in both groups . No significant differences in demographic or clinical features were observed between RA patients carrying the MIF 173C allele or the MIF catt7 allele or both and non carrier RA patients . radiologic joint damage …

Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor. (1998 Aug)
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 .

Macrophage migration inhibitory factor ( MIF ) promotes fibroblast migration in scratch wounded monolayers in vitro. (2007 Sep)
macrophage migration inhibitory factor ( MIF ) promotes fibroblast migration in scratch wounded monolayers in vitro . MIF was recently redefined as an inflammatory cytokine , which functions as a critical mediator of diseases such as septic shock , rheumatoid arthritis , atherosclerosis , and cancer . MIF also regulates wound healing processes . given that fibroblast migration is a central event in wound healing and that MIF was recently demonstrated to promote leukocyte migration through an interaction with G protein coupled receptors , we investigated the effect of MIF on fibroblast migration in wounded monolayers in vitro . transient but not permanent exposure of primary mouse or human fibroblasts with MIF significantly promoted wound closure , a response that encompassed both a proliferative and a pro migratory component . importantly , MIF induced fibroblast activation was accompanied by an induction of calcium signalling , whereas chronic exposure with MIF down regulated the calcium transient , suggesting receptor desensitization as the underlying mechanism .

Mechanisms of disease : macrophage migration inhibitory factor in SLE , RA and atherosclerosis. (2008 Jan)
mechanisms of disease : macrophage migration inhibitory factor in SLE , RA and atherosclerosis . The past decade has seen the emergence of two new paradigms in inflammatory disease : first , cardiovascular complications of atherosclerosis are markedly increased in patients with rheumatoid arthritis ( RA ) and systemic lupus erythematosus ( SLE ) ; and second , inflammatory mechanisms are important in the pathogenesis of atherosclerosis . these concurrent developments have lead to the concept that inflammatory mediators operative in RA and SLE might be causal in the accelerated atherosclerosis observed , a concept supported by clinical studies showing that this acceleration is not fully explained by traditional vascular risk factors . separate lines of evidence implicate the cytokine macrophage migration inhibitory factor ( MIF ) in RA , SLE , and atherosclerosis . several reports have revealed definitive in vivo evidence of the activity of MIF in a model of SLE , demonstrated a novel role for MIF in monocyte / macrophage recruitment , and showed that MIF regulates a key mediator of inflammatory cell activation . together with evidence that MIF circulates in increased concentrations in patients with RA and SLE , this information suggests that in addition to contributing to each disease , MIF might contribute directly to the acceleration of atherosclerosis in RA and SLE .

New therapeutic target in inflammatory disease : macrophage migration inhibitory factor. (2005 Jun)
New therapeutic target in inflammatory disease : macrophage migration inhibitory factor . The cytokine macrophage migration inhibitory factor ( MIF ) participates in fundamental events in innate and adaptive immunity . The profile of activities of MIF in vivo and in vitro is strongly suggestive of a role for MIF in the pathogenesis of many inflammatory diseases , including rheumatoid arthritis ( RA ) , and hence antagonism of MIF is suggested as a potential therapeutic strategy in inflammatory disease . The best developed case for therapeutic antagonism of MIF is in RA . In RA , MIF is abundantly expressed in serum and synovial tissue . MIF induces synovial expression of key pro inflammatory genes , regulates the function of endothelial cells and leucocytes , and is implicated in the control of synoviocyte proliferation and apoptosis via direct effects on the expression of the tumour suppressor protein p53 . In animal models of RA , anti MIF antibodies or genetic MIF deficiency are associated with significant inhibition of disease . A similar case has been made , for example using MIF deficient mice , in models of atheroma , colitis , multiple sclerosis and other inflammatory diseases . The relationship with p53 also means MIF may be important in the link between inflammatory disease and cancer , such as is seen in RA or colitis . MIF also has a unique relationship with glucocorticoids , in that despite antagonizing their effects , the expression of MIF is in fact …

Role of macrophage migration inhibitory factor ( MIF ) in murine antigen induced arthritis : interaction with glucocorticoids. (2001 Mar)
Role of macrophage migration inhibitory factor ( MIF ) in murine antigen induced arthritis : interaction with glucocorticoids . ( MIF ) is a broad spectrum proinflammatory cytokine implicated in human rheumatoid arthritis . The synthesis of MIF by synovial cells is stimulated by glucocorticoids , and previous studies suggest that MIF antagonizes the anti inflammatory effects of glucocorticoids . This has not been established in a model of arthritis . We wished to test the hypothesis that MIF can act to reverse the anti inflammatory effects of glucocorticoids in murine antigen induced arthritis ( AIA ) . cutaneous DTH reactions and AIA were induced by intradermal injection and intra articular injection , respectively , of methylated bovine serum albumin in presensitized mice . animals were treated with anti MIF moabs , recombinant MIF , and / or dexamethasone ( DEX ) . Skin thickness of DTH reactions was measured with callipers and arthritis severity was measured by blinded quantitative histological assessment of synovial cellularity . cutaneous DTH to the disease initiating antigen was significantly inhibited by anti MIF MoAb treatment ( P 0 . 001 ) . AIA was also significantly inhibited by anti MIF MoAb ( P 0 . 02 ) . DEX treatment induced a dose dependent inhibition of AIA , which was significant at 0 . 2 mg / kg ( P 0 . 05 ) . MIF treatment reversed the effect of therapeutic DEX on AIA ( P 0 . 001 ) . DEX also …

Newer uses of glucose insulin potassium regimen. (2001 Mar)
newer uses of glucose insulin potassium regimen . diabetic ketoacidosis and moderate degree of hyperglycemia can be managed by glucose insulin potassium ( GIK ) regimen . The GIK regimen is also useful in the treatment of acute myocardial infarction ( AMI ) . But , the exact mechanism ( s ) of the beneficial action of GIK regimen is not known . I suggest that glucose insulin can suppress the secretion and antagonize the harmful effects of tumor necrosis factor alpha ( TNF alpha ) and macrophage migration inhibitory factor ( MIF ) . If this is true , it suggests that GIK regimen may be useful in septicemia and septic shock , and other inflammatory conditions such as ulcerative colitis , crohn s disease , rheumatoid arthritis , systemic lupus erythematosus and cancer , conditions in which TNF alpha and MIF appear to play a major role .

Pathophysiological roles of macrophage migration inhibitory factor in gastrointestinal , hepatic , and pancreatic disorders. (2005 Mar)
pathophysiological roles of macrophage migration inhibitory factor in gastrointestinal , hepatic , and pancreatic disorders . macrophage migration inhibitory factor ( MIF ) is a unique protein , participating in inflammation , immune response , and cell growth . MIF was first discovered as a lymphokine involved in delayed hypersensitivity and various macrophage functions , including phagocytosis , spreading , and tumoricidal activity . It has been reported that MIF is associated with the pathogenesis of a variety of diseases . MIF expression was increased at inflammatory sites in diseases such as rheumatoid arthritis and glomerulonephritis . In experimental inflammatory disease , blockade of MIF bioactivity inhibited the severity of disease activity . On the other hand , MIF expression is also increased in tumor lesions , and MIF plays a role as a cell growth factor . MIF has been reported to be constitutively expressed in gut , liver , and pancreas . In patients with gastritis , inflammatory bowel disease , hepatitis , and pancreatitis , MIF expression was remarkably increased in both the serum and the local lesions . blockade of MIF bioactivity inhibited and prevented inflammation in experimental gastritis , colitis , hepatitis , and pancreatitis . On the other hand , MIF expression was higher than that in normal tissues in colonic carcinomas and hepatocellular carcinoma both in vivo and in vitro . blockade of MIF bioactivity successfully inhibited tumor cell growth in vivo and in vitro . MIF plays important roles in the pathogenesis …

Macrophage migration inhibitory factor ( MIF ) and oligoarticular juvenile idiopathic arthritis ( o JIA ) : association of MIF … (2007 Dec)
macrophage migration inhibitory factor ( MIF ) and oligoarticular juvenile idiopathic arthritis ( o JIA ) : association of MIF promoter polymorphisms with response to intra articular glucocorticoids . objectives : To address the clinical relevance of macrophage migration inhibitory factor ( MIF ) promoter polymorphisms in oligoarticular juvenile idiopathic arthritis ( o JIA ) by evaluating their associations with serum and SF MIF levels , with response to intra articular glucocorticoid injections and with outcome of the disease . methods : seventy five caucasian patients with o JIA were studied . alleles of the 794 CATT variable number of tandem repeats ( VNTR ) and of the 173 G / C single nucleotide polymorphism ( SNP ) were identified by capillary electrophoresis following fluorescently labelled PCR and by allelic discrimination assay , respectively . MIF levels were measured by elisa . The association of MIF promoter polymorphisms with polyarticular extension , childhood health assessment questionnaire ( CHAQ ) score at the last follow up visit and occurrence of chronic anterior uveitis was evaluated only in patients with a follow up 5 years . results : neither of the MIF promoter polymorphisms was associated with serum MIF levels , nor with the long term outcome of o JIA . The 173 G / C SNP was significantly associated with both SF MIF levels and duration of response to intra articular glucocorticoid injection . carriers of a MIF 173 C allele were 4 times more likely to relapse within 3 months …

Macrophage migration inhibitory factor : gene polymorphisms and susceptibility to inflammatory diseases. (2005 Oct)
macrophage migration inhibitory factor : gene polymorphisms and susceptibility to inflammatory diseases . The cytokine macrophage migration inhibitory factor ( MIF ) is a constitutive element of the host antimicrobial defenses and stress response that promotes proinflammatory function of the innate and acquired immune systems . MIF plays an important role in the pathogenesis of acute and chronic inflammatory or autoimmune disorders , such as sepsis , acute respiratory distress syndrome , asthma , rheumatoid arthritis , and inflammatory bowel diseases . polymorphisms of the human MIF gene ( that is , guanine to cytosine transition at position 173 or CATT tetranucleotide repeat at position 794 ) have been associated with increased susceptibility to or severity of juvenile idiopathic and adult rheumatoid arthritis , ulcerative colitis , atopy , or sarcoidosis . whether these MIF polymorphisms affect the susceptibility to and outcome of sepsis has not yet been examined . analyses of MIF genotypes in patients with sepsis may help to classify patients into risk categories and to identify those patients who may benefit from anti MIF therapeutic strategies .