Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophage migration inhibitory factor (MIF) has a multitude of biological activity and is associated with a number of inflammatory and immune diseases, including rheumatoid arthritis (RA). The increased serum levels of MIF in patients not only suggest this protein as a marker for disease progression, but also as a potential therapeutic target. The aim of this study is to develop a novel electrochemical method to more precisely and conveniently measure MIF in patient sera. An IgM murine monoclonal antibody (mAb) against human MIF was prepared and used in the electrochemical immunosensor, with modified gold electrode coated with compounds of gold nanoparticles, titanium dioxide nanoparticles and thionine (NGP-NTiP-Thi) followed by adsorption of anti-MIF antibodies with IgM or IgG1 isotype. The IgM immunosensor recognized MIF in a linear relationship in the range of 0.03 and 230 ng/mL with the lower limit (S/N=3) of 0.02 ng/mL. The measurement showed considerable levels of sensitivity, selectivity, stability and long-term maintenance of bioactivity, as shown by testing with serum MIF in RA patients as compared to healthy donors. The performance of the IgM immunosensor was also superior to IgG1 sensor. Thus, we have developed a novel measurement approach for serum MIF, which may have great potential in the clinic for monitoring the course of diseases associated with increased MIF.
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PMID:Development of a novel method to measure macrophage migration inhibitory factor (MIF) in sera of patients with rheumatoid arthritis by combined electrochemical immunosensor. 1844 90

Polymorphisms within the gene encoding macrophage migration inhibitory factor (MIF) have been associated with susceptibility to inflammatory diseases such as rheumatoid arthritis and increased risk of developing sepsis. We investigated the effects of the MIF-173G>C polymorphism and the MIF-794 CATT microsatellite on MIF expression. These are in moderate linkage disequilibrium. Mononuclear cells from healthy donors were stimulated with bacterial pathogens associated with sepsis (Streptococcus pneumoniae or Escherichia coli ). MIF mRNA and protein levels were measured by real-time polymerase chain reaction and ELISA, respectively. Carriage of the C allele of MIF-173G>C or the 7 CATT repeat of the MIF-794 microsatellite correlated with lower basal and stimulated MIF mRNA levels. However, levels of intracellular and extracellular MIF protein were similar. This discordance between effects on MIF mRNA and protein was not explained by differential effects of genotype on stability of MIF mRNA (detected by actinomycin D mRNA chase). Gel shift assays revealed no differences in the profile of nuclear proteins from mononuclear cells bound by the G and C alleles of MIF-173G>C, but alleles at the microsatellite marker showed differential binding. Our data suggest that the MIF-794 CATT microsatellite influences transcription by differential binding of nuclear transcription factors. This may impact on inflammatory processes.
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PMID:The microsatellite, macrophage migration inhibitory factor -794, may influence gene expression in human mononuclear cells stimulated with E. coli or S. pneumoniae. 1868 May 14

Originally discovered and named as an in vitro inhibitor of macrophage migration, the cytokine macrophage migration inhibitory factor (MIF) has now been shown to be a key regulator of acute and chronic immuno-inflammatory conditions including rheumatoid arthritis (RA), atherosclerosis, and more recently systemic lupus erythematosus (SLE). Common inflammatory events in these diseases include activation of cells and infiltration by immune cells at the site of injury. MIF actively participates in multiple stages of the inflammatory response, acting on cells directly and/or potentiating the effects entrained by other stimuli. The overlap of inflammatory processes operating in these diseases, the known activities of MIF, and the observation of atherosclerosis as a major comorbidity of RA and SLE, make MIF a strong candidate for therapeutic targeting in these diseases. Moreover, the unique relationship between MIF and glucocorticoids, commonly used in the treatment of RA and SLE but associated with significant side effects, highlights the potential of MIF as a 'steroid sparing' therapeutic target encompassing all three conditions.
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PMID:Macrophage migration inhibitory factor: a key cytokine in RA, SLE and atherosclerosis. 1883 66

Deposition of immune complexes (IC) triggers Fc gamma R-dependent inflammation, leading to tissue damage in rheumatoid arthritis, systemic lupus erythematous, immune glomerulonephritis, and several immune vasculitides. Evidences support a role for macrophage migration inhibitory factor (MIF) in a number of inflammatory diseases, but the triggering of its secretion and its physiopathological role upon IC deposition remain elusive. Herein, we show that human macrophages secreted MIF after IC recognition, which in turn controlled the secretion of TNF. Macrophages from Mif-/- mice produced smaller amounts of TNF when stimulated with IgG-opsonized erythrocytes than wild-type (WT) cells. Using passive reverse Arthus reaction in the peritoneum and lungs as a model for IC-induced inflammation, we demonstrated that Mif-/- mice had a milder response, observed by reduced neutrophil recruitment, vascular leakage, and secretion of TNF, MIP-2, and keratinocyte-derived chemokine compared with WT controls. Adoptive transfer of alveolar macrophages from WT to Mif-/- mice rescued pulmonary neutrophil recruitment and TNF production upon passive reverse Arthus reaction. Our study indicates that Arthus inflammatory reaction is largely dependent on MIF and poses macrophages as a source of the MIF released upon IC recognition. These results give experimental support to the proposition that blockade of MIF might constitute an adjunctive, therapeutic approach to IC disease.
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PMID:Migration inhibitory factor (MIF) released by macrophages upon recognition of immune complexes is critical to inflammation in Arthus reaction. 1918 84

Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
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PMID:Glucocorticoid resistance in inflammatory diseases. 1948 16

An array of investigations has revealed that macrophage migration inhibitory factor (MIF) plays an important role in the exacerbation of a wide range of inflammatory diseases. For the past two decades, we have extensively studied MIF's pathophysiological roles in human diseases, and have accumulated evidence elucidating its molecular mechanisms in the pathogenesis of immune disorders and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel diseases (IBD). In a study of IBD, we demonstrated for the first time that anti-MIF antibody suppressed the degree of dextran-sulfate sodium (DSS)-induced colitis, indicating its potential therapeutic use for IBD patients. Following that report, a number of researchers, including us, clarified that MIF was profoundly involved in various gastrointestinal disorders, such as hepatitis and pancreatitis. We recently revealed that a MIF-deficient mouse was resistant to a challenge of DSS, and showed few clinical and pathological signs. Currently, we are developing new therapeutic approaches targeting MIF in inflammatory disorders, particularly IBD. We here overview MIF's pathophysiological function, mainly in IBD, and introduce two therapeutic approaches, anti-MIF antibody treatment and MIF-antisense therapy, via a drug delivery system using 1,3-beta glucan.
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PMID:Overview of the role of macrophage migration inhibitory factor (MIF) in inflammatory bowel disease. 1951 41

Osteoporosis is a severe condition in postmenopausal women and a common cause of fracture. Osteoporosis is a complex disease with a strong genetic impact, but susceptibility is determined by many genes with modest effects and environmental factors. Only a handful of genes consistently associated with osteoporosis have been identified so far. Inflammation affects bone metabolism by interfering with the interplay between bone resorption and formation, and many inflammatory mediators are involved in natural bone remodeling. The cytokine macrophage migration inhibitory factor (MIF) has been shown to affect bone density in rodents, and polymorphisms in the human MIF promoter are associated with inflammatory disorders such as rheumatoid arthritis. We investigated the association of polymorphisms in the MIF gene with bone mineral density (BMD) and bone loss in 1002 elderly women using MIF promoter polymorphisms MIF-CATT(5-8) and rs755622(G/C) located -794 and -173 bp upstream of the transcriptional start site. Bone loss was estimated both by the change in BMD over 5 years and by the levels of bone resorption markers in serum measured at four occasions during a 5-year period. The MIF-CATT(7)/rs755622(C) haplotype was associated with increased rate of bone loss during 5 years at the femoral neck (p<0.05) and total hip (p<0.05). In addition, the MIF-CATT(7)/rs755622(C) haplotype carriers had higher levels of the bone turnover marker serum C-terminal cross-linking telopeptide of type I collagen (S-CTX-I, p<0.01) during the 5 year follow-up period. There was no association between MIF-CATT(7)/rs755622(C) and baseline BMD at femoral neck, total hip or lumbar spine. We conclude that MIF promoter polymorphisms have modest effects on bone remodeling and are associated with the rate of bone loss in elderly women.
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PMID:Polymorphisms in the macrophage migration inhibitory factor gene and bone loss in postmenopausal women. 2047 6

Elucidation of factors regulating glucocorticoid (GC) sensitivity is required for the development of "steroid-sparing" therapies for chronic inflammatory diseases, including rheumatoid arthritis (RA). Accumulating evidence suggests that macrophage migration inhibitory factor (MIF) counterregulates the GC-induction of anti-inflammatory mediators, including mitogen-activated protein kinase phosphatase 1 (MKP1), a critical mitogen-activated protein kinase signaling inhibitor. This observation has yet to be extended to human disease; the molecular mechanisms remain unknown. We investigated NURR1, a GC-responsive transcription factor overexpressed in RA, as a MIF signaling target. We reveal abrogation by recombinant MIF (rMIF) of GC-induced MKP1 expression in RA fibroblast-like synoviocytes (FLS). rMIF enhanced NURR1 expression, artificial NBRE (orphan receptor DNA-binding site) reporter transactivation, and reversed GC-inhibition of NURR1. NURR1 expression was reduced during experimental arthritis in MIF-/- synovium, and silencing MIF reduced RA FLS NURR1 mRNA. Consistent with NBRE identification on the MKP1 gene, MKP1 mRNA was reduced in FLS that ectopically express NURR1, and silencing NURR1 enhanced MKP1 mRNA in RA FLS. rMIF enhanced NBRE binding on the MKP1 gene, and the absence of the NBRE prevented NURR1-repressive effects on basal and GC-induced MKP1 transactivation. This study defines NURR1 as a novel MIF target in chronic inflammation and demonstrates a role for NURR1 in regulating the anti-inflammatory mediator, MKP1. We propose a MIF-NURR1 signaling axis as a regulator of the GC sensitivity of MKP1.
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PMID:Identification of NURR1 as a mediator of MIF signaling during chronic arthritis: effects on glucocorticoid-induced MKP1. 2082 34

The aim of this study was to determine the genetic regulation of macrophage migration inhibitory factor (MIF). DNase I hypersensitivity was used to identify potential hypersensitive sites (HS) across the MIF gene locus. Reporter gene assays were performed in different human cell lines with constructs containing the native or mutated HS element. Following phylogenetic and transcription factor binding profiling, electrophoretic mobility shift assay (EMSA) and RNA interference were performed and the effects of incubation with mithramycin, an antibiotic that binds GC boxes, were also studied. An HS centred on the first intron of MIF was identified. The HS acted as an enhancer in human T lymphoblasts (CEMC7A), human embryonic kidney cells (HEK293T) and human monocytic cells (THP-1), but not in a fibroblast-like synoviocyte (FLS) cell line (SW982) or cultured FLS derived from rheumatoid arthritis (RA) patients. Two cis-elements within the first intron were found to be responsible for the enhancer activity. Mutation of the consensus Sp1 GC box on each cis-element abrogated enhancer activity and EMSA indicated Sp1 binding to one of the cis-elements contained in the intron. SiRNA knock-down of Sp1 alone or Sp1 and Sp3 together was incomplete and did not alter the enhancer activity. Mithramycin inhibited expression of MIF in CEMC7A cells. This effect was specific to the intronic enhancer and was not seen on the MIF promoter. These results identify a novel, cell type-specific enhancer of MIF. The enhancer appears to be driven by Sp1 or related Sp family members and is highly sensitive to inhibition via mithramycin.
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PMID:Identification of a novel cell type-specific intronic enhancer of macrophage migration inhibitory factor (MIF) and its regulation by mithramycin. 2108 45

Owing to its implication in a range of pathological conditions, including asthma, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and cancer, the pleiotropic cytokine macrophage migration inhibitory factor (MIF) has been the subject of intensive recent investigation. In the field of dermatology, MIF is believed to be a detrimental factor in diseases such as systemic sclerosis, atopic dermatitis, psoriasis, eczema and UV radiation damage. However, its contribution to other aspects of cutaneous biology is currently unclear. Although its expression in intact skin is well characterized, little is known about MIF's role in cutaneous homoeostasis. However, recent data do identify MIF as a key player in the immune privilege of hair follicles. Similarly, although MIF is rapidly released and its local expression significantly induced upon wounding, its primary role in the ensuing repair process remains a source of contention. MIF has been identified as being a key effector of the beneficial effects of estrogen on wound repair, yet studies employing Mif null mice, recombinant MIF, and neutralizing anti-MIF antibodies have failed to provide a consensus as to whether it benefits or inhibits healing. In fact MIF appears to be able to exert both positive and negative effects, with the cell-specific relevancy of MIF in wound healing still unclear. Thus, if MIF and/or its downstream targets are to be therapeutically useful in the context of cutaneous repair, more needs to be done to establish the nature and mechanism of action of MIF and its receptors in healing wounds.
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PMID:MIF: a key player in cutaneous biology and wound healing. 2115 33


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