scholarly journals Intravesical CD74 and CXCR4, macrophage migration inhibitory factor (MIF) receptors, mediate bladder pain

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255975
Author(s):  
Shaojing Ye ◽  
Fei Ma ◽  
Dlovan F. D. Mahmood ◽  
Katherine L. Meyer-Siegler ◽  
Raymond E. Menard ◽  
...  
Keyword(s):  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
High Mobility ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Urothelial Cells ◽  
Bladder Pain ◽  
Pre Treatment

Background Activation of intravesical protease activated receptor 4 (PAR4) leads to release of urothelial macrophage migration inhibitory factor (MIF). MIF then binds to urothelial MIF receptors to release urothelial high mobility group box-1 (HMGB1) and elicit bladder hyperalgesia. Since MIF binds to multiple receptors, we investigated the contribution of individual urothelial MIF receptors to PAR4-induced HMGB1 release in vivo and in vitro and bladder pain in vivo. Methodology/Principal findings We tested the effect of intravesical pre-treatment with individual MIF or MIF receptor (CD74, CXCR4, CXCR2) antagonists on PAR4-induced HMGB1 release in vivo (female C57/BL6 mice) and in vitro (primary human urothelial cells) and on PAR4-induced bladder hyperalgesia in vivo (mice). In mice, PAR4 induced HMGB1 release and bladder hyperalgesia through activation of intravesical MIF receptors, CD74 and CXCR4. CXCR2 was not involved in these effects. In primary urothelial cells, PAR4-induced HMGB1 release through activation of CD74 receptors. Micturition parameters in mice were not changed by any of the treatments. Conclusions/Significance Urothelial MIF receptors CD74 and CXCR4 mediate bladder pain through release of urothelial HMGB1. This mechanism may set up persistent pain loops in the bladder and warrants further investigation. Urothelial CD74 and CXCR4 may provide novel targets for interrupting bladder pain.

scholarly journals Oxygen regulation of macrophage migration inhibitory factor in human placenta

2007 ◽  
Vol 292 (1) ◽  
pp. E272-E280 ◽  
Author(s):  
Francesca Ietta ◽  
Yuanhong Wu ◽  
Roberta Romagnoli ◽  
Nima Soleymanlou ◽  
Barbara Orsini ◽  
...  
Keyword(s):  
High Altitude ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
Extravillous Trophoblast ◽  
Macrophage Migration ◽  
Low Oxygen ◽  
Placental Development

Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine involved in regulation of macrophage function. In addition, MIF may also play a role in murine and human reproduction. Although both first trimester trophoblast and decidua express MIF, the regulation and functional significance of this cytokine during human placental development remains unclear. We assessed MIF expression throughout normal human placental development, as well as in in vitro (chorionic villous explants) and in vivo (high altitude placentae) models of human placental hypoxia. Dimethyloxalylglycine (DMOG), which stabilizes hypoxia inducible factor-1 under normoxic conditions, was also used to mimic the effects of hypoxia on MIF expression. Quantitative real-time PCR and Western blot analysis showed high MIF protein and mRNA expression at 7–10 wk and lower levels at 11–12 wk until term. Exposure of villous explants to 3% O2 resulted in increased MIF expression and secretion relative to standard conditions (20% O2). DMOG treatment under 20% O2 increased MIF expression. In situ hybridization and immunohistochemistry showed elevated MIF expression in low oxygen-induced extravillous trophoblast cells. Finally, a significant increase in MIF transcript was observed in placental tissues from high-altitude pregnancies. Hence, three experimental models of placental hypoxia (early gestation, DMOG treatment, and high altitude) converge in stimulating increased MIF, supporting the conclusion that placental-derived MIF is an oxygen-responsive cytokine highly expressed in physiological in vivo and in in vitro low oxygen conditions.

scholarly journals Substance P Increases Cell-Surface Expression of CD74 (Receptor for Macrophage Migration Inhibitory Factor): In Vivo Biotinylation of Urothelial Cell-Surface Proteins

2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Katherine L. Meyer-Siegler ◽  
Shen-Ling Xia ◽  
Pedro L. Vera
Keyword(s):  
Substance P ◽  
Cell Surface ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Urothelial Cell ◽  
Inhibitory Factor ◽  
Cell Surface Expression ◽  
Macrophage Migration ◽  
Urothelial Cells

Macrophage migration inhibitory factor (MIF), an inflammatory cytokine, and its receptor CD74 are upregulated by bladder inflammation. MIF-mediated signal transduction involves binding to cell-surface CD74, this study documents, in vivo, MIF-CD74interactions at the urothelial cell surface. N-hydroxysulfosuccinimide biotin ester-labeled surface urothelial proteins in rats treated either with saline or substance P (SP, 40 μg/kg). The bladder was examined by histology and confocal microscopy. Biotinylated proteins were purified by avidin agarose, immunoprecipitated with anti-MIF or anti-CD74 antibodies, and detected with strepavidin-HRP. Only superficial urothelial cells were biotinylated. These cells contained a biotinylated MIF/CD74 cell-surface complex that was increased in SP-treated animals. SP treatment increased MIF and CD74 mRNA in urothelial cells. Our data indicate that intraluminal MIF, released from urothelial cells as a consequence of SP treatment, interacts with urothelial cell-surface CD74. These results document that our previously described MIF-CD74 interaction occurs at the urothelial cell surface.

scholarly journals Elevated Levels of the Plasmodium yoelii Homologue of Macrophage Migration Inhibitory Factor Attenuate Blood-Stage Malaria

2010 ◽  
Vol 78 (12) ◽  
pp. 5151-5162 ◽  
Author(s):  
Swati Thorat ◽  
Thomas M. Daly ◽  
Lawrence W. Bergman ◽  
James M. Burns
Keyword(s):  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Plasmodium Yoelii ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Proinflammatory Response ◽  
Necrosis Factor Alpha

ABSTRACT The excessive production of proinflammatory cytokines plays a significant role in the pathogenesis of severe malaria. Mammalian macrophage migration inhibitory factor (MIF) (mMIF) is an immune mediator that promotes a sustained proinflammatory response by inhibiting the glucocorticoid-mediated downregulation of inflammation. In addition, Plasmodium parasites also encode a homologue of mammalian MIF that is expressed in asexual-stage parasites. We used the Plasmodium yoelii murine model to study the potential role of parasite-encoded MIF in the pathogenesis of malaria. Antibodies raised against purified, non-epitope-tagged P. yoelii MIF (PyMIF) were used to localize expression in trophozoite- and schizont-stage parasites and demonstrate extracellular release. In vitro, recombinant PyMIF was shown to actively induce the chemotaxis of macrophages but did not induce or enhance tumor necrosis factor alpha (TNF-α) production from peritoneal macrophages. To examine the role of parasite-derived PyMIF in vivo, two transgenic parasite lines that constitutively overexpress PyMIF were generated, one in a nonlethal P. yoelii 17X background [Py17X-MIF(+)] and the other in a lethal P. yoelii 17XL background [Py17XL-MIF(+)]. Challenge studies with transgenic parasites in mice showed that the increased expression of PyMIF resulted in a reduction in disease severity. Mice infected with Py17X-MIF(+) developed lower peak parasitemia levels than controls, while malaria-associated anemia was unaltered. Infection with Py17XL-MIF(+) resulted in a prolonged course of infection and a reduction in the overall mortality rate. Combined, the data indicate that parasite-derived MIF does not contribute significantly to immunopathology but, through its chemotactic ability toward macrophages, may attenuate disease and prolong infection of highly virulent parasite isolates.

scholarly journals Macrophage migration inhibitory factor is essential for osteoclastogenic mechanisms in vitro and in vivo mouse model of arthritis

Cytokine ◽  
2015 ◽  
Vol 72 (2) ◽  
pp. 135-145 ◽  
Author(s):  
Ran Gu ◽  
Leilani L. Santos ◽  
Devi Ngo ◽  
HuaPeng Fan ◽  
Preetinder P. Singh ◽  
...  
Keyword(s):  
Mouse Model ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
Macrophage Migration

scholarly journals Macrophage migration inhibitory factor facilitates the therapeutic efficacy of mesenchymal stem cells derived exosomes in acute myocardial infarction through upregulating miR-133a-3p

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Wenwu Zhu ◽  
Ling Sun ◽  
Pengcheng Zhao ◽  
Yaowu Liu ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Cardiomyocyte Apoptosis ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Protective Function ◽  
H9c2 Cardiomyocytes ◽  
Cardioprotective Effects

Abstract Background Exosome transplantation is a promising cell-free therapeutic approach for the treatment of ischemic heart disease. The purpose of this study was to explore whether exosomes derived from Macrophage migration inhibitory factor (MIF) engineered umbilical cord MSCs (ucMSCs) exhibit superior cardioprotective effects in a rat model of AMI and reveal the mechanisms underlying it. Results Exosomes isolated from ucMSCs (MSC-Exo), MIF engineered ucMSCs (MIF-Exo) and MIF downregulated ucMSCs (siMIF-Exo) were used to investigate cellular protective function in human umbilical vein endothelial cells (HUVECs) and H9C2 cardiomyocytes under hypoxia and serum deprivation (H/SD) and infarcted hearts in rats. Compared with MSC-Exo and siMIF-Exo, MIF-Exo significantly enhanced proliferation, migration, and angiogenesis of HUVECs and inhibited H9C2 cardiomyocyte apoptosis under H/SD in vitro. MIF-Exo also significantly inhibited cardiomyocyte apoptosis, reduced fibrotic area, and improved cardiac function as measured by echocardiography in infarcted rats in vivo. Exosomal miRNAs sequencing and qRT-PCR confirmed miRNA-133a-3p significantly increased in MIF-Exo. The biological effects of HUVECs and H9C2 cardiomyocytes were attenuated with incubation of MIF-Exo and miR-133a-3p inhibitors. These effects were accentuated with incubation of siMIF-Exo and miR-133a-3p mimics that increased the phosphorylation of AKT protein in these cells. Conclusion MIF-Exo can provide cardioprotective effects by promoting angiogenesis, inhibiting apoptosis, reducing fibrosis, and preserving heart function in vitro and in vivo. The mechanism in the biological activities of MIF-Exo involves miR-133a-3p and the downstream AKT signaling pathway.

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