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Nodding syndrome (NS) is a catastrophic and enigmatic childhood epilepsy, accompanied by multiple neurological impairments and neuroinflammation. Of all the infectious, environmental and psychological factors associated with NS, the major culprit is Onchocerca Volvulus (Ov)-a parasitic worm transmitted to human by blackflies. NS seems to be an 'Autoimmune Epilepsy' in light of the recent findings of deleterious autoimmune antibodies to Glutamate receptors and to Leiomodin-I in NS patients. Moreover, we recently found immunogenetic fingerprints in HLA peptide-binding grooves associate with protection or susceptibility to NS. Macrophage migration inhibitory factor (MIF) is an immune-regulatory cytokine playing a central role in modulating innate and adaptive immunity. MIF is also involved in various pathologies: infectious, autoimmune and neurodegenerative diseases, epilepsy and others. Herein, two functional polymorphisms in the MIF gene, a -794 CATT5-8 microsatellite repeat and a -173 G/C single-nucleotide polymorphism, were assessed in 49 NS patients and 51 healthy controls from South Sudan. We also measured MIF plasma levels in established NS patients and healthy controls. We discovered that the frequency of the high-expression MIF -173C containing genotype was significantly lower in NS patients compared to healthy controls. Interestingly however, MIF plasma levels were significantly elevated in NS patients than in healthy controls. We further demonstrated that the HLA protective and susceptibility associations are dominant over the MIF association with NS. Our findings suggest that MIF might have a dual role in NS. Genetically controlled high-expression MIF genotype is associated with disease protection. However, elevated MIF in the plasma may contribute to the detrimental autoimmunity, neuroinflammation and epilepsy.
Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine involved in many cellular processes and in particular carcinogenesis. Here, we review the experimental and clinical published data on MIF and its pathways in breast cancer. Experimental data show that MIF is overexpressed in breast cancer cells (BCC) due, at least partly, to its stabilization by HSP90 and upregulation by HIF-1α. MIF interacts with its main receptor CD74 and its co-receptor CXCR-4, both overexpressed, promoting cell survival by PI3K/Akt activation, a possible link with EGFR and HER2 pathways and inhibition of autophagy. Besides these auto- and paracrine effects on BCC, MIF interacts with BCC microenvironment by several mechanisms: immunomodulation by increasing the prevalence of immune suppressive cells, neo-angiogenesis by its link to HIF-1, and finally BCC transendothelial migration. Clinical studies show higher levels of MIF in breast cancer patients serum compared to healthy volunteers but without obvious clinical significance. In breast cancer tissue, MIF and CD74 are overexpressed in the cancer cells and in the stroma but correlations with classical prognostic factors or survival are elusive. However, an inverse correlation with the tumor size for stromal MIF and a positive correlation with the triple receptor negative tumor status for stromal CD74 seem to be showed. This set of experimental and clinical data shows the involvement of MIF pathways in breast carcinogenesis. Several anti-MIF targeted strategies are being explored in therapeutic goals and should merit further investigations.
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and has been implicated in inflammatory diseases. However, little is known about the regulation of MIF in adipose tissue and its impact on wound healing. The aim of this study was to investigate MIF expression in inflamed adipose and determine its role in inflammatory cell recruitment and wound healing. Adipose tissue was harvested from subcutaneous adipose tissue layers of 24 healthy subjects and from adipose tissue adjacent to acutely inflamed wounds of 21 patients undergoing wound debridement. MIF protein and mRNA expression were measured by ELISA and RT-PCR. Cell-specific MIF expression was visualized by immunohistochemistry. The functional role of MIF in cell recruitment was investigated by a chemotaxis assay and by flow cytometry of labeled macrophages that were injected into Mif-/-and wildtype mice. Wound healing was evaluated by an in vitro scratch assay on human fibroblast monolayers. MIF protein levels of native adipose tissue and supernatants from acutely inflamed wounds were significantly elevated when compared to healthy controls. MIF mRNA expression was increased in acutely inflamed adipose tissue indicating the activation of MIF gene transcription in response to adipose tissue inflammation. MIF is expressed in mature adipocytes and in infiltrated macrophages. Peripheral blood mononuclear cell migration was significantly increased towards supernatants derived from inflamed adipose tissue. This effect was partially abrogated by MIF-neutralizing antibodies. Moreover, when compared to wildtype mice, Mif-/-mice showed reduced infiltration of labeled macrophages into LPS-stimulated epididymal fat pads in vivo. Finally, MIF antibodies partially neutralized the detrimental effect of MIF on fibroblast wound healing. Our results indicate that increased MIF expression and rapid activation of the MIF gene in fat tissue adjacent to acute wound healing disorders may play a role in cell recruitment to the site of inflammation and wound healing.
Macrophage migration inhibitory factor (MIF) is a proinflammatory molecule in mammals that, unusually for a cytokine, exhibits tautomerase and oxidoreductase enzymatic activities. Homologues of this well conserved protein are found within diverse phyla including a number of parasitic organisms. Herein, we produced recombinant histidine-tagged Toxoplasma gondii MIF (TgMIF), a 12-kDa protein that lacks oxidoreductase activity but exhibits tautomerase activity with a specific activity of 19.3 μmol/min/mg that cannot be inhibited by the human MIF inhibitor ISO-1. The crystal structure of the TgMIF homotrimer has been determined to 1.82 Å, and although it has close structural homology with mammalian MIFs, it has critical differences in the tautomerase active site that account for the different inhibitor sensitivity. We also demonstrate that TgMIF can elicit IL-8 production from human peripheral blood mononuclear cells while also activating ERK MAPK pathways in murine bone marrow-derived macrophages. TgMIF may therefore play an immunomodulatory role during T. gondii infection in mammals.
Macrophage migration inhibitory factor (MIF) is pleiotropic cytokine that has multiple effects in many inflammatory and immune diseases. This study reveals a potential role of MIF in acute kidney injury (AKI) in patients and in kidney ischemic reperfusion injury (IRI) mouse model in MIF wild-type (WT) and MIF knockout (KO) mice. Clinically, plasma and urinary MIF levels were largely elevated at the onset of AKI, declined to normal levels when AKI was resolved and correlated tightly with serum creatinine independent of disease causes. Experimentally, MIF levels in plasma and urine were rapidly elevated after IRI-AKI and associated with the elevation of serum creatinine and the severity of tubular necrosis, which were suppressed in MIF KO mice. It was possible that MIF may mediate AKI via CD74/TLR4-NF-κB signalling as mice lacking MIF were protected from AKI by largely suppressing CD74/TLR-4-NF-κB associated renal inflammation, including the expression of MCP-1, TNF-α, IL-1β, IL-6, iNOS, CXCL15(IL-8 in human) and infiltration of macrophages, neutrophil, and T cells. In conclusion, our study suggests that MIF may be pathogenic in AKI and levels of plasma and urinary MIF may correlate with the progression and regression of AKI.
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.
Uveal melanoma is a rare melanoma subtype different from cutaneous melanoma, with high incidence of liver metastasis and poor prognosis. Cancer cell-derived extracellular vesicles have been shown to induce proinflammatory and prometastatic signaling in the tumor microenvironment and at distant sites. The characterization of uveal melanoma exosome cargo and its role in metastatic spread is essential to identify targets and intervene in the early stages of metastatic development. Our study characterizes the proteomic content of uveal melanoma exosomes and identified the presence of markers with metastatic properties. We demonstrated that uveal melanoma exosomes induce activation of cell signaling pathways and the release of cytokines and growth factors from hepatocytes. These exosome-stimulated liver cells could in turn induce migration of uveal melanoma cells, confirming that the exosomes have a functional role in the cross-talk between these two cell types. We found that the proinflammatory cytokine macrophage migration inhibitory factor (MIF) was a major player in these mechanisms and its blockade inhibited cell migration in coculture with exosome-stimulated hepatocytes and prevented the development of metastases in vivo. Targeting MIF in the early stages of metastasis may represent a novel adjuvant drug therapy to prevent metastatic spread in uveal melanoma.
The present study aimed to observe the content difference of macrophage migration inhibitory factor [MIF; novoprotein recombinant human MIF (n‑6his) (ch33)], TGFβ1 and MMP13 in patients with and without ligamentum flavum (LF) hypertrophy and investigate the roles of MIF in LF hypertrophy. The concentration of MIF, TGFβ1 and MMP13 in LF were detected by ELISA in a lumbar spinal stenosis (LSS) group and a lumbar disc herniation (LDH) group. Culture of primary LFs and identification were performed for the subsequent study. Cell treatments and cell proliferation assay by CCK‑8 was performed. Western blot and quantitative PCR analysis were used to detect the expression of TGFβ1, MMP13, type I collagen (COL‑1) and type III collagen (COL‑3) and Src which were promoted by MIF. The concentration of MIF, TGFβ1 and MMP13 were higher in the LSS group compared with the LDH group. Culture of primary LFs and identification were performed. Significant difference in LFs proliferation occurred with treatment by MIF at a concentration of 40 nM for 48 h (P<0.05). The gene and protein expression of TGFβ1, MMP13, COL‑1, COL‑3 and Src were promoted by MIF (P<0.05). Proliferation of LFs was induced by MIF and MIF‑induced proliferation of LFs was inhibited by PP1 (a Src inhibitor). MIF may promote the proliferation of LFs through the Src kinase signaling pathway and can promote extracellular matrix changes by its pro‑inflammatory effect. MIF and its mediated inflammatory reaction are driving factors of LF hypertrophy.
Trichomonas vaginalis is responsible for the most prevalent non-viral sexually transmitted disease worldwide, and yet the mechanisms used by this parasite to establish and maintain infection are poorly understood. We previously identified a T. vaginalis homologue (TvMIF) of a human cytokine, human macrophage migration inhibitory factor (huMIF). TvMIF mimics huMIF's role in increasing cell growth and inhibiting apoptosis in human host cells. To interrogate a role of TvMIF in parasite survival during infection, we asked whether overexpression of TvMIF (TvMIF-OE) confers an advantage to the parasite under nutrient stress conditions by comparing the survival of TvMIF-OE parasites to that of empty vector (EV) parasites. We found that under conditions of serum starvation, overexpression of TvMIF resulted in increased parasite survival. Serum-starved parasites secrete 2.5-fold more intrinsic TvMIF than unstarved parasites, stimulating autocrine and paracrine signaling. Similarly, we observed that addition of recombinant TvMIF increased the survival of the parasites in the absence of serum. Recombinant huMIF likewise increased the parasite survival in the absence of serum, indicating that the parasite may use this host survival factor to resist its own death. Moreover, TvMIF-OE parasites were found to undergo significantly less apoptosis and reactive oxygen species (ROS) generation under conditions of serum starvation, consistent with increased survival being the result of blocking ROS-induced apoptosis. These studies demonstrated that a parasitic MIF enhances survival under adverse conditions and defined TvMIF and huMIF as conserved survival factors that exhibit cross talk in host-pathogen interactions.IMPORTANCE Macrophage migration inhibitory factor (MIF) is a conserved protein found in most eukaryotes which has been well characterized in mammals but poorly studied in other eukaryotes. The limited analyses of MIF proteins found in unicellular eukaryotes have focused exclusively on the effect of parasitic MIF on the mammalian host. This was the first study to assess the function of a parasite MIF in parasite biology. We demonstrate that the Trichomonas vaginalis MIF functions to suppress cell death induced by apoptosis, thereby enhancing parasite survival under adverse conditions. Our research reveals a conserved survival mechanism, shared by a parasite and its host, and indicates a role for a conserved protein in mediating cross talk in host-pathogen interactions.
Endometriosis, a disease of reproductive age women, is a major cause of infertility, menstrual disorders and pelvic pain. Little is known about its etiopathology, but chronic pelvic inflammation is a common feature in affected women. Beside symptomatic treatment of endometriosis-associated pain, only two main suboptimal therapeutic approaches (hormonal and invasive surgery) are generally recommended to patients and no specific targeted treatment is available. Our studies led to the detection of a marked increase in the expression of macrophage migration inhibitory factor (MIF) in the eutopic endometrium, the peripheral blood and the peritoneal fluid of women with endometriosis, and in early, vascularized and active endometriotic lesions. Herein, we developed a treatment model of endometriosis, where human endometrial tissue was first allowed to implant into the peritoneal cavity of nude mice, to assess in vivo the effect of a specific antagonist of MIF (ISO-1) on the progression of endometriosis and evaluate its efficacy as a potential therapeutic tool. Administration of ISO-1 led to a significant decline of the number, size and in situ dissemination of endometriotic lesions. We further showed that ISO-1 may act by significantly inhibiting cell adhesion, tissue remodeling, angiogenesis and inflammation as well as by altering the balance of pro- and anti-apoptotic factors. Actually, mice treatment with ISO-1 significantly reduced the expression of cell adhesion receptors αv and ß3 integrins (P<0.05), matrix metalloproteinases (MMP) 2 and 9 (P<0.05), vascular endothelial cell growth factor (VEGF) (P<0.01), interleukin 8 (IL8) (P<0.05), cyclooxygenease (COX)2 (P<0.001) and the anti-apoptotic protein Bcl2 (P<0.01), but significantly induced the expression of Bax (P<0.05), a potent pro-apoptotic protein. These data provide evidence that specific inhibition of MIF alters endometriotic tissue growth and progression in vivo and may represent a promising potential therapeutic avenue.
The beneficial functions of mesenchymal stem cells (MSCs) decline with age, limiting their therapeutic efficacy for myocardial infarction (MI). Macrophage migration inhibitory factor (MIF) promotes cell proliferation and survival. We investigated whether MIF overexpression could rejuvenate aged MSCs and increase their therapeutic efficacy in MI. Young and aged MSCs were isolated from the bone marrow of young and aged donors. Young MSCs, aged MSCs, and MIF-overexpressing aged MSCs were transplanted into the peri-infarct region in a rat MI model. Aged MSCs exhibited a lower proliferative capacity, lower MIF level, greater cell size, greater senescence-associated-β-galactosidase activity, and weaker paracrine effects than young MSCs. Knocking down MIF in young MSCs induced cellular senescence, whereas overexpressing MIF in aged MSCs reduced cellular senescence. MIF rejuvenated aged MSCs by activating autophagy, an effect largely reversed by the autophagy inhibitor 3-methyladenine. MIF-overexpressing aged MSCs induced angiogenesis and prevented cardiomyocyte apoptosis to a greater extent than aged MSCs, and had improved heart function and cell survival more effectively than aged MSCs four weeks after MI. Thus, MIF rejuvenated aged MSCs by activating autophagy and enhanced their therapeutic efficacy in MI, suggesting a novel MSC-based therapeutic strategy for cardiovascular diseases in the aged population.
Astrocytes, the major glial cell population of the central nervous system (CNS), play important physiological roles related to CNS homeostasis. Growing evidence demonstrates that astrocytes trigger innate immune responses under challenge of a variety of proinflammatory cytokines. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine mainly secreted from monocytes/macrophages, is involved in inflammation-associated pathophysiology. Here, we displayed that expression of MIF significantly increased following spinal cord injury, in colocalization with microglia and astrocytes. MIF elicited inflammatory responses of astrocytes via activation of CD74 receptor and extracellular signal-related kinase (ERK) pathway. Transcriptome analysis revealed that inflammation-related factors cholesterol 25-hydroxylase (Ch25h) and phospholipase A2-IIA (Pla2g2a), downstream of MIF/CD74 axis, were potentially implicated in the mediating inflammatory response of astrocytes. Our results provided a new target for interference of CNS inflammation after insults.
Macrophage migration inhibitory factor (MIF), a small conserved protein, is abundant in the immune- and central nervous system (CNS). MIF has several receptors and binding partners that can modulate its action on a cellular level. It is upregulated in neurodegenerative diseases and cancer although its function is far from clear. Here, we report the finding of a new binding partner to MIF, the serine protease HTRA1. This enzyme cleaves several growth factors, extracellular matrix molecules and is implicated in some of the same diseases as MIF. We show that the function of the binding between MIF and HTRA1 is to inhibit the proteolytic activity of HTRA1, modulating the availability of molecules that can change cell growth and differentiation. MIF is therefore the first endogenous inhibitor ever found for HTRA1. It was found that both molecules were present in astrocytes and that the functional binding has the ability to modulate astrocytic activities important in development and disease of the CNS.
Background: Adipose-derived stem cells (ASCs) are multipotent mesenchymal stem cells characterized by their strong regenerative potential and low oxygen consumption. Macrophage migration inhibitory factor (MIF) is a multifunctional chemokine-like cytokine that is involved in tissue hypoxia. MIF is not only a major immunomodulator but also is highly expressed in adipose tissue such as subcutaneous adipose tissue of chronic non-healing wounds. In the present study, we investigated the effect of hypoxia on MIF in ASCs isolated from healthy versus inflamed adipose tissue. Methods: Human ASCs were harvested from 17 patients (11 healthy adipose tissue samples, six specimens from chronic non-healing wounds). ASCs were treated in a hypoxia chamber at <1% oxygen. ASC viability, MIF secretion as well as expression levels of MIF, its receptor CD74, hypoxia-inducible transcription factor-1α (HIF-1α) and activation of the AKT and ERK signaling pathways were analyzed. The effect of recombinant MIF on the viability of ASCs was determined. Finally, the effect of MIF on the viability and production capacity of ASCs to produce the inflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1β was determined upon treatment with recombinant MIF and/or a blocking MIF antibody. Results: Hypoxic treatment inhibited proliferation of ASCs derived from healthy or chronic non-healing wounds. ASCs from healthy adipose tissue samples were characterized by a low degree of MIF secretion during hypoxic challenge. In contrast, in ASCs from adipose tissue samples of chronic non-healing wounds, secretion and expression of MIF and CD74 expression were significantly elevated under hypoxia. This was accompanied by enhanced ERK signaling, while AKT signaling was not altered. Recombinant MIF did stimulate HIF-1α expression under hypoxia as well as AKT and ERK phosphorylation, while no effect on ASC viability was observed. Recombinant MIF significantly reduced the secretion of IL-1β under hypoxia and normoxia, and neutralizing MIF-antibodies diminished TNF-α and IL-1β release in hypoxic ASCs. Conclusions: Collectively, MIF did not affect the viability of ASCs from neither healthy donor site nor chronic wounds. Our results, however, suggest that MIF has an impact on the wound environment by modulating inflammatory factors such as IL-1β.
The mechanism of the neuroprotective effect of the macrophage migration inhibitory factor (MIF) in vivo is unclear. We investigated whether the MIF promotes neurological recovery in an in vivo mouse model of ischemic stroke. Transient middle cerebral artery occlusion (MCAO) surgery was performed to make ischemic stroke mouse model. Male mice were allocated to a sham vehicle, a sham MIF, a middle cerebral artery occlusion (MCAO) vehicle, and MCAO+MIF groups. Transient MCAO (tMCAO) was performed in the MCAO groups, and the vehicle and the MIF were administered via the intracerebroventricular route. We evaluated the neurological functional scale, the rotarod test, and T2-weighted magnetic resonance imaging. The expression level of the microtubule-associated protein 2 (MAP2), Bcl2, and the brain-derived neurotrophic factor (BDNF) were further measured by Western blot assay. The Garcia test was significantly higher in the MCAO+MIF group than in the MCAO+vehicle group. The MCAO+MIF group exhibited significantly better performance on the rotarod test than the MCAO+vehicle group, which further had a significantly reduced total infarct volume on T2-weighted MRI imaging than the MCAO vehicle group. Expression levels of BDNF, and MAP2 tended to be higher in the MCAO+MIF group than in the MCAO+vehicle group. The MIF exerts a neuroprotective effect in an in vivo ischemic stroke model. The MIF facilitates neurological recovery and protects brain tissue from ischemic injury, indicating a possibility of future novel therapeutic agents for stroke patients.
Although MEK blockade has been highlighted as a promising antitumor drug, it has poor clinical efficacy in KRAS mutant colorectal cancer (CRC). Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single-MEK targeted therapies. Here, we investigated a bypass mechanism of resistance to MEK inhibition in KRAS CRC. We found that KRAS mutant CRC cells with refametinib, MEK inhibitor, induced MIF secretion and resulted in activation of STAT3 and MAPK. MIF knockdown by siRNA restored sensitivity to refametinib in KRAS mutant cells. In addition, combination with refametinib and 4-IPP, a MIF inhibitor, effectively reduced the activity of STAT3 and MAPK, more than single-agent treatment. As a result, combined therapy was found to exhibit a synergistic growth inhibitory effect against refametinib-resistant cells by inhibition of MIF activation. These results reveal that MIF-induced STAT3 and MAPK activation evoked an intrinsic resistance to refametinib. Our results provide the basis for a rational combination strategy against KRAS mutant colorectal cancers, predicated on the understanding of cross talk between the MEK and MIF pathways.
Macrophage migration inhibitory factor (MIF) is a cytokine that mediates the interaction between malignant cells and the innate immune system. Recently, MIF has received attention for its role in tumorigenesis. We evaluated the prognostic role of MIF in clear cell renal cell carcinoma (CCRCC).A total of 152 patients, who underwent nephrectomy for CCRCC were enrolled in this study. Immunohistochemical staining of tissue microarray blocks containing 298 cores-2 cores per CCRCC patient was performed. The relationship between MIF expression and clinicopathological factors was evaluated. Total RNA and protein were extracted from 7 RCC (renal cell carcinoma) cell lines. MIF was knocked down in Caki-2 cells, and a wound healing assay was performed to evaluate migratory activity.Among the 298 cores, 180 (60.4%) were positive for MIF. Multivariate analysis, showed that, CCRCC patients with negative MIF expression exhibited poor disease-free survival (hazard ratio: 2.087, 95% confidence interval: 0.821-5.307, P value: .023) and poor disease-specific survival (hazard ratio: 2.101, 95% confidence interval: 1.009-4.374, P value: .047). The wound healing assay revealed that cell confluence was lower in MIF-deficient Caki-2 cells than in control cells.Negative MIF expression might be an independent prognostic marker for patients with CCRCC.
Triple-negative breast cancer (TNBC), defined as loss of estrogen, progesterone, and Her2 receptors, is a subtype of highly aggressive breast cancer with worse prognosis and poor survival rate. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine aberrantly expressed in many solid tumors and known to promote tumor progression and metastasis. However, its role in TNBC progression and metastasis is unexplored. Here we have shown that in TNBC patients, MIF expression was significantly enriched in the tumor compared to adjacent normal tissue. Using publically available patient datasets, we showed that MIF overexpression correlates with worse survival in TNBC compared to other hormonal status. Orthotopic implantation of TNBC cells into MIF knockout mice showed reduced tumor growth compared to wild-type mice. In addition, we have shown that MIF downregulation inhibits TNBC growth and progression in a syngeneic mouse model. We further showed that CPSI-1306, a small-molecule MIF inhibitor, inhibits the growth of TNBC cells in vitro. Mechanistic studies revealed that CPSI-1306 induces intrinsic apoptosis by alteration in mitochondrial membrane potential, cytochrome c (Cyt c) release, and activation of different caspases. In addition, CPSI-1306 inhibits the activation of cell survival and proliferation-related molecules. CPSI-1306 treatment also reduced the tumor growth and metastasis in orthotopic mouse models of mammary carcinoma. CPSI-1306 treatment of tumor-bearing mice significantly inhibited TNBC growth and pulmonary metastasis in a dose-dependent manner. Histological analysis of xenograft tumors revealed a higher number of apoptotic cells in CPSI-1306-treated tumors compared to vehicle controls. Our studies, for the first time, show that MIF overexpression in TNBC enhances growth and metastasis. Taken together, our results indicate that using small molecular weight MIF inhibitors could be a promising strategy to inhibit TNBC progression and metastasis.
Macrophage Migration Inhibitory Factor (MIF) is an inflammatory cytokine that is highly produced in gastrointestinal cancers. Since chronic inflammation is a risk factor for tumorigenesis in these cancers, in this study, the role of MIF in pro-tumorigenic events was examined. MIF and its receptor, CD74, were examined in gastric and colon tumors and found to be increased in most tumors with significantly higher expression in tumors from patients with lymph node metastasis. MIF was also found to be highly produced by cancer associated fibroblasts isolated from human tumors compared to fibroblasts from matched normal tissues from uninvolved areas. Fibroblast-produced MIF highly increased GI cancer cell proliferation, which was decreased upon neutralizing MIF or CD74. Chronic MIF treatment led to sustained proliferation and signaling events in non-transformed GI fibroblast cells, which was maintained upon removing MIF treatment for 8 weeks. Additionally, chronic treatment of normal GI cells expressing fibroblast markers for up to 16 weeks with MIF led to a drastic decrease of fibroblast markers with concurrent increase of epithelial markers. Transformation was examined by telomerase and focus forming assays. These results suggest the MIF promotes mesenchymal epithelial transition, cell transformation and tumorigenesis in GI cancers, and thus may be an important link between chronic inflammation and tumorigenesis.
Macrophage migration inhibitory factor (MIF) and GTPase dynamin-related protein 1 (Drp1)-dependent aberrant mitochondrial fission are closely linked to the pathogenesis of asthma. However, it is unclear whether Drp1-mediated mitochondrial fission and its downstream targets mediate MIF-induced proliferation of airway smooth muscle cells (ASMCs) in vitro and airway remodeling in chronic asthma models. The present study aims to clarify these issues.
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