Macrophage migration inhibitory factor (MIF) in the development and progression of pulmonary arterial hypertension.
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ABSTRACT:
SUBMITTER: Ahmed M
PROVIDER: S-EPMC6062764 | biostudies-other | 2018 Jun
REPOSITORIES: biostudies-other
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Macrophage migration inhibitory factor (MIF) in the development and progression of pulmonary arterial hypertension.
Ahmed Mohamed M Miller Edmund E
Global cardiology science & practice 20180630 2
Macrophage migration inhibitory factor (MIF) has been described as a pro-inflammatory cytokine and regulator of neuro-endocrine function. It plays an important upstream role in the inflammatory cascade by promoting the release of other inflammatory cytokines such as TNF-alpha and IL-6, ultimately triggering a chronic inflammatory immune response. As lungs can synthesize and release MIF, many studies have investigated the potential role of MIF as a biomarker in assessment of patients with pulmona ...[more]
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Project description:BACKGROUND:Pulmonary hypertension (PH) is a common complication of idiopathic pulmonary fibrosis (IPF) that significantly contributes to morbidity and mortality. Macrophage migration inhibitory factor (MIF) is a critical factor in vascular remodeling of the pulmonary circulation. OBJECTIVES:We tested the effects of two small molecules targeting MIF on bleomycin (BLM)-induced collagen deposition, PH, and vascular remodeling in mouse lungs. METHODS:We examined the distribution pattern of MIF, CD74, and CXCR4 in the lungs of patients with IPF-PH and the lungs of BLM-injected mice. Then, treatments were realized with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and N-(3-hydroxy-4-fluorobenzyl)-5 trifluoromethylbenzoxazol-2-thione 31 (20 mg/kg/day per os for 3 weeks) started 24 h after an intratracheal BLM administration. RESULTS:More intense immunoreactivity was noted for MIF, CD74, and CXCR4 in lungs from IPF-PH patients and BLM-injected mice. Furthermore, we found that treatments of BLM-injected mice with ISO-1 or compound 31 attenuated lung collagen deposition and right ventricular systolic pressure increase. Additionally, reduced pulmonary inflammatory infiltration and pulmonary arterial muscularization were observed in the lungs of BLM-injected mice treated with ISO-1 or compound 31. CONCLUSIONS:Treatments with ISO-1 or compound 31 attenuates BLM-induced inflammation and fibrosis in lung, and prevents PH development in mice, suggesting that MIF is an important factor for IPF-PH development.
| S-EPMC6321607 | biostudies-literature
Project description:The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity, which contributes to the biological functional activity of MIF. In this study, we investigated the effects of blocking the hydrophobic active site of the tautomerase activity of MIF in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumor growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (Mif (P1G)). Primary tumor growth was significantly attenuated in both Mif-KO and Mif (P1G) mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for the tautomerase enzymatic active site of MIF. From primary and secondary screens, the inhibitor SCD-19 was identified, which significantly attenuated the tautomerase enzymatic activity of MIF in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumor inoculation, was found to significantly reduce primary tumor volume by 90% (p < 0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumor was palpable (at d 7 after tumor inoculation) and, again, treatment was found to significantly reduce tumor volume by 81% (p < 0.001) compared with the control treatment. In this report, we identify a novel inhibitor that blocks the hydrophobic pocket of MIF, which houses its specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in vivo systems.
| S-EPMC4398672 | biostudies-literature
Project description:Macrophage migration inhibitory factor (MIF) is a catalytic cytokine and an upstream mediator of the inflammatory pathway. MIF has broad regulatory properties, dysregulation of which has been implicated in the pathology of multiple immunological diseases. Inhibition of MIF activity with small molecules has proven beneficial in a number of disease models. Known small molecule MIF inhibitors typically bind in the tautomerase site of the MIF trimer, often covalently modifying the catalytic proline. Allosteric MIF inhibitors, particularly those that associate with the protein by noncovalent interactions, could reveal novel ways to block MIF activity for therapeutic benefit and serve as chemical probes to elucidate the structural basis for the diverse regulatory properties of MIF. In this study, we report the identification and functional characterization of a novel allosteric MIF inhibitor. Identified from a high throughput screening effort, this sulfonated azo compound termed p425 strongly inhibited the ability of MIF to tautomerize 4-hydroxyphenyl pyruvate. Furthermore, p425 blocked the interaction of MIF with its receptor, CD74, and interfered with the pro-inflammatory activities of the cytokine. Structural studies revealed a unique mode of binding for p425, with a single molecule of the inhibitor occupying the interface of two MIF trimers. The inhibitor binds MIF mainly on the protein surface through hydrophobic interactions that are stabilized by hydrogen bonding with four highly specific residues from three different monomers. The mode of p425 binding reveals a unique way to block the activity of the cytokine for potential therapeutic benefit in MIF-associated diseases.
| S-EPMC3436310 | biostudies-literature
Project description:The immunomodulator Macrophage Migration Inhibitory Factor (MIF) exerts pleiotropic immunomodulatory activities and has been implicated in the pathogenesis of diverse inflammatory diseases. Expression levels of MIF are also significantly elevated in the skin and serum of psoriasis patients, but the pathogenic significance of MIF in psoriasis is unknown. We have therefore addressed the role of MIF in two mouse models of psoriasis, namely in the imiquimod-induced psoriasiform dermatitis (IIPD) and the IL-23-induced dermatitis model. Daily treatment with Aldara™ cream, containing imiquimod, markedly increased the abundance of MIF in the skin and generated a cellular skin expression pattern of MIF closely resembling that in human plaque psoriasis. Deficiency in MIF significantly alleviated IIPD. On the clinical level, all hallmarks of psoriasiform dermatitis, including erythema, skin infiltration, and desquamation were reduced in Mif -/- mice. On the histopathological level, MIF deficiency decreased keratinocyte hyperproliferation, inflammatory cell infiltration, specifically with respect to monocyte-derived cells, and dermal angiogenesis, suggesting that MIF may be involved in the pathogenesis of psoriasiform dermatitis through several mechanisms. Similarly, MIF deficiency also significantly reduced disease in the IL-23-induced dermatitis model, suggesting that MIF is involved in the pathogenic pathways activated by IL-23 and required to achieve full-blown psoriasiform dermatitis. Collectively, our results lend support to a possible disease-promoting role of MIF in psoriasis, which should be further investigated.
| S-EPMC6176003 | biostudies-literature
Project description:BackgroundMacrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and mediator of acute and chronic inflammatory diseases. MIF is overexpressed in various tumours and has been suggested as a molecular link between chronic inflammation and cancer. MIF overexpression is observed in breast cancer but its causal role in the development of this tumour entity is unclear.MethodsMIF levels in breast cancer cell lines were determined by ELISA and Western blot. CD74 was measured by Western blot, fluorescence microscopy and flow cytometry. Cell proliferation was studied by BrdU incorporation, cell adhesion by Matrigel adhesion assay, and cell invasion by migration assay through Matrigel-coated filters using the Transwell system. MIF expression in primary human breast cancers was measured by tissue microarray and a semi-quantitative immunoreactivity score (IRS) and comparison with histopathological parameters and patient outcome data.ResultsMIF was abundantly expressed in the non-invasive breast cancer cell lines MDA-MB-468 and ZR-75-1, but not in invasive MDA-MB-231 cells, which in turn expressed higher levels of the MIF-receptor CD74. Stimulation with exogenous MIF led to a dramatic upregulation of MIF secretion (50-fold) in MDA-MB-231 cells. Autocrine MIF promoted tumour cell proliferation, as indicated by blockade of MIF or CD74 in MDA-MB-231 and MDA-MB-468, and MDA-MB-231 invasiveness was enhanced by exogenous MIF. We correlated the expression of MIF with histopathological parameters and patient outcome data, using a tissue microarray of 175 primary invasive breast cancers and 35 normal control tissues. MIF was upregulated in breast cancer versus normal tissue (median IRS = 8 versus 6). MIF expression showed positive correlations with progesterone (p = 0.006) and estrogen (p = 0.028) receptor expression, markers of a favourable prognosis and a negative correlation to tumour size (p = 0.007). In line with these data, disease-specific overall (OS) as well as recurrence-free (RFS) survival was significantly improved in breast cancer patients with abundant cytosolic MIF expression compared to MIF low expressers (5-year OS = 67% versus 50%, p = 0.0019; 5-year RFS = 52% versus 36%, p = 0.0327).ConclusionWe conclude that intracellular expression of MIF in breast cancer cells is beneficial, whereas extracellular MIF may play a pro-oncogenic role in promoting breast cancer cell-stroma interactions.
| S-EPMC2716369 | biostudies-literature
Project description:Recurrence in patients with glioblastoma (GBM) is inevitable resulting in short survival times, even in patients with O-6-Methylguanine-DNA Methyltransferase (MGMT) methylation. Other pathways must be activated to escape from temozolomide (TMZ) treatment, however acquired resistance mechanisms to TMZ are not well understood. Herein, frozen tumors from 36 MGMT methylated patients grouped according to overall survival were extracted and proteins were profiled using surface-enhanced laser desorption/ionization (SELDI) with time-of flight (TOF) proteomics to identify low molecular weight proteins that associated with poor survival outcomes. Overexpression of macrophage migration inhibitory factor (MIF) was identified in human GBM specimens that were MGMT methylated but showed poor survival. This correlation was confirmed in an independent cohort of human GBM. MIF overexpression has been reported in several cancer types, including GBM. We repurposed ibudilast, a specific MIF inhibitor, and treated patient derived cell lines. Ibudilast showed modest anti-proliferative activity however, when combined with TMZ, significant synergism was observed, resulting in cell cycle arrest and apoptosis. In vivo, combined ibudilast and TMZ treatment of a patient derived xenograft (PDX) model resulted in significantly longer overall survival. Our findings have significant clinical implications for people with GBM. Since clinical trials involving ibudilast have shown no adverse side effects and the drug readily penetrates the blood brain barrier, treatment of GBM with this combination is clinically achievable.
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Project description:MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]) is a pro-inflammatory cytokine expressed in multiple cells types, including macrophages. MIF plays a pathogenic role in a number of inflammatory diseases and has been linked to tumor progression in some cancers. Previous work has demonstrated that loss of autophagy in macrophages enhances secretion of IL1 family cytokines. Here, we demonstrate that loss of autophagy, by pharmacological inhibition or siRNA silencing of Atg5, enhances MIF secretion by monocytes and macrophages. We further demonstrate that this is dependent on mitochondrial reactive oxygen species (ROS). Induction of autophagy with MTOR inhibitors had no effect on MIF secretion, but amino acid starvation increased secretion. This was unaffected by Atg5 siRNA but was again dependent on mitochondrial ROS. Our data demonstrate that autophagic regulation of mitochondrial ROS plays a pivotal role in the regulation of inflammatory cytokine secretion in macrophages, with potential implications for the pathogenesis of inflammatory diseases and cancers.
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Project description:PurposeRecent studies have demonstrated that macrophage migration inhibitory factor (MIF) is of importance in asthmatic inflammation. The role of MIF in modulating airway remodeling has not yet been thoroughly elucidated to date. In the present study, we hypothesized that MIF promoted airway remodeling by intensifying airway smooth muscle cell (ASMC) autophagy and explored the specific mechanisms.MethodsMIF knockdown in the lung tissues of C57BL/6 mice was conducted by instilling intratracheally adeno-associated virus (AAV) vectors (MIF-mutant AAV9) into mouse lung tissues. Mice genetically deficient in the autophagy marker ATG5 (ATG5+/-) was used to detect the role of autophagy in ovalbumin (OVA)-asthmatic murine models. Moreover, to block the expression of MIF and CD74 in vitro models, inhibitors, antibodies and lentivirus transfection techniques were employed.ResultsFirst, MIF knockdown in the lung tissues of mice showed markedly reduced airway remodeling in OVA murine mice models. Secondly, ASMC autophagy was increased in the OVA-challenged models. Mice genetically deficient in the autophagy marker ATG5 (ATG5+/-) that were primed and challenged with OVA showed lower airway remodeling than genetically wild-type asthmatic mice. Thirdly, MIF can induce ASMC autophagy in vitro. Moreover, the cellular source of MIF which promoted ASMC autophagy was macrophages. Finally, MIF promoted ASMC autophagy in a CD74-dependent manner.ConclusionsMIF can increase asthmatic airway remodeling by enhancing ASMC autophagy. Macrophage-derived MIF can promote ASMC autophagy by targeting CD74.
| S-EPMC7680835 | biostudies-literature
Project description:BackgroundMacrophage migration inhibitory factor (MIF) is an important immuno-regulatory cytokine and is elevated in inflammatory conditions. Neutrophils are the first immune cells to migrate to sites of infection and inflammation, where they generate, among other mediators, the potent oxidant hypochlorous acid (HOCl). Here, we investigated the impact of MIF on HOCl production in neutrophils in response to phagocytic stimuli.MethodsProduction of HOCl during phagocytosis of zymosan was determined using the specific fluorescent probe R19-S in combination with flow cytometry and live cell microscopy. The rate of phagocytosis was monitored using fluorescently-labeled zymosan. Alternatively, HOCl production was assessed during phagocytosis of Pseudomonas aeruginosa by measuring the oxidation of bacterial glutathione to the HOCl-specific product glutathione sulfonamide. Formation of neutrophil extracellular traps (NETs), an oxidant-dependent process, was quantified using a SYTOX Green plate assay.ResultsExposure of human neutrophils to MIF doubled the proportion of neutrophils producing HOCl during early stages of zymosan phagocytosis, and the concentration of HOCl produced was greater. During phagocytosis of P. aeruginosa, a greater fraction of bacterial glutathione was oxidized to glutathione sulfonamide in MIF-treated compared to control neutrophils. The ability of MIF to increase neutrophil HOCl production was independent of the rate of phagocytosis and could be blocked by the MIF inhibitor 4-IPP. Neutrophils pre-treated with MIF produced more NETs than control cells in response to PMA.ConclusionOur results suggest a role for MIF in potentiating HOCl production in neutrophils in response to phagocytic stimuli. We propose that this newly discovered activity of MIF contributes to its role in mediating the inflammatory response and enhances host defence.
| S-EPMC8047225 | biostudies-literature
Project description:The presence of activated pancreatic stellate cells (PSCs) in the pancreatic ductal adenocarcinoma (PDAC) microenvironment plays a significant role in cancer progression. Macrophage migration inhibitory factor (MIF) is overexpressed in PDAC tissues and expressed by both cancer and stromal cells. The expression status of MIF and its receptors in PDAC- associated fibroblasts or PSCs and its pathophysiological roles are yet to be elucidated. The next-generation sequencing technique was adapted to check the effect of MIF absence on the expression of other genes in mice (mPSCs).
2022-09-28 | E-MTAB-9392 | biostudies-arrayexpress