The effect of soluble CD74 (sCD74) and recombinant macrophage migration inhibitory factor (MIF) treatment on the gene expression profile in cardiac myofibroblasts
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PROVIDER: PRJNA429369 | ENA |
REPOSITORIES: ENA
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Project description:Co-treatment with soluble CD74 and MIF induced necroptosis in cardiac myofibroblasts. The underlying mechanism of sCD74/MIF-induced necroptosis are still unkown. We used a microarray to identify pathways regulated by co-treatment with sCD74 and MIF .
2018-11-06 | GSE108999 | GEO
Project description:Background Although macrophage migration inhibitory factor ( MIF ) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD 74, the function of the soluble CD 74 receptor ectodomain ( sCD 74) and its interaction with circulating MIF have not been explored in cardiac disease. Methods and Results Cardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co-treatment with recombinant MIF and sCD 74 induced cell death ( P<0.001), which was mediated by receptor-interacting serine/threonine-protein kinase ( RIP) 1/ RIP 3-dependent necroptosis ( P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT - qPCR technology revealed a 4-fold upregulation of several interferon-induced genes upon co-treatment of myofibroblasts with sCD 74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD 74 as a modulator of MIF signaling by diminishing MIF -mediated protein kinase B ( AKT) activation ( P=0.0197) and triggering p38 activation ( P=0.0641). We obtained evidence that sCD 74 inhibits MIF -mediated survival pathway through the C-X-C chemokine receptor 4/ AKT axis, enabling the induction of CD 74-dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD 74/ MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244). Conclusions These findings suggest that treatment of cardiac myofibroblasts with sCD 74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD 74/ MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.
| S-EPMC6201423 | biostudies-literature
Project description:NIH 3T3 fibroblasts that express little detectable levels of the MIF binding receptor CD74 but do express the signalling component CD44 were used for the identification of interacting proteins that are shared by MIF and D-DT. Endogenously expressed MIF and D-DT were tagged at the C-terminus using a short sequence that is recognized and biotinylated by the bacterial biotin ligase BirA (Efficient biotinylation and single-step purification of tagged transcription factors in mammalian cells and transgenic mice. Proc. Natl. Acad. Sci. U. S. A. 100, 7480–5) as described in detail for MIF Filip, A. M. et al. (2009). Ribosomal Protein S19 Interacts with Macrophage Migration Inhibitory Factor and Attenuates Its Pro-inflammatory Function. J. Biol. Chem. 284, 7977–7985). After pulling down biotinylated proteins from stable NIH 3T3 clones that express tagged MIF or D-DT and BirA ligase with streptavidin agarose, bound proteins were separated by SDS-PAGE and identified after elution and tryptic digestion by mass spectrometry in order to characterize the MIF and D-DT interactomes.
2021-01-27 | PXD020449 | Pride
Project description:CD74 (invariant chain), expressed on B cells, is directly involved in shaping the B cell repertoire by regulating their survival in health and disease. Binding of its ligand, macrophage migration inhibitory factor (MIF), induces a cascade that results in CD74 intramembrane proteolysis, and the release of the CD74 intracellular domain (CD74-ICD). CD74-ICD translocates to the nucleus where it induces activation of transcription. In the current study, we characterized the transcription factor activity of CD74-ICD. Following histone modifications we are able to characterize CD74's binding sites as regulatory areas.
2022-11-03 | GSE181676 | GEO
Project description:Lasting B-cell persistence depends on survival signals that are transduced by cell surface receptors. Here, we describe a novel biological mechanism essential for survival and homeostasis of normal peripheral mature B cells and chronic lymphocytic leukemia (CLL) cells, regulated by the heparin-binding cytokine, midkine (MK), and its proteoglycan receptor, the receptor-type tyrosine phosphatase zeta (RPTPζ). We demonstrate that MK initiates a signaling cascade leading to B cell survival, by binding to RPTPζ. In mice lacking PTPRZ, the proportion and number of the mature B cell population is reduced. Our results emphasize a unique and critical function for MK signaling in the previously described MIF/CD74 induced survival pathway. Stimulation of CD74 with MIF leads to c-Met activation, resulting in elevation of MK expression in both normal mouse splenic B and CLL cells. Our results indicate that MK and RPTPζ are important regulators of the B cell repertoire. These findings could pave the way towards understanding the mechanisms shaping B cell survival, and suggest novel therapeutic strategies based on the blockade of the midkine/RPTPζ-dependent survival pathway. 2 samples were incubated with or without MIF.
2011-11-01 | E-GEOD-33352 | biostudies-arrayexpress
Project description:Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+ B lymphocytes in peripheral blood, lymphoid organs and BM. The main feature of the disease is accumulation of the malignant cells due to decreased apoptosis. CD84 belongs to the Signaling Lymphocyte Activating Molecule (SLAM) family of immunoreceptors, and has an unknown function in CLL cells. Here, we show that the expression of CD84 is significantly elevated from the early stages of the disease, and is regulated by macrophage migration inhibitory factor (MIF) and its receptor, CD74. Activation of cell surface CD84 initiates a signaling cascade that enhances CLL cell survival. Both immune-mediated neutralization or blockade of CD84 induce cell death in vitro and in vivo. In addition, analysis of samples derived from an on-going clinical trial, in which human subjects were treated with humanized anti-CD74 milatuzumab shows a decrease in CD84 mRNA levels milatuzumab-treated cells. This downregulation was correlated with reduction of Bcl-2 and Mcl-1 message. Thus, our data show that overexpression of CD84 in CLL is an important survival mechanism that appears to be an early event in the pathogenesis of the disease. These findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway. 3 samples; incubated with PBS, MIF, or IL-8.
2013-03-01 | E-GEOD-37430 | biostudies-arrayexpress
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
Project description:Lasting B-cell persistence depends on survival signals that are transduced by cell surface receptors. Here, we describe a novel biological mechanism essential for survival and homeostasis of normal peripheral mature B cells and chronic lymphocytic leukemia (CLL) cells, regulated by the heparin-binding cytokine, midkine (MK), and its proteoglycan receptor, the receptor-type tyrosine phosphatase zeta (RPTPζ). We demonstrate that MK initiates a signaling cascade leading to B cell survival, by binding to RPTPζ. In mice lacking PTPRZ, the proportion and number of the mature B cell population is reduced. Our results emphasize a unique and critical function for MK signaling in the previously described MIF/CD74 induced survival pathway. Stimulation of CD74 with MIF leads to c-Met activation, resulting in elevation of MK expression in both normal mouse splenic B and CLL cells. Our results indicate that MK and RPTPζ are important regulators of the B cell repertoire. These findings could pave the way towards understanding the mechanisms shaping B cell survival, and suggest novel therapeutic strategies based on the blockade of the midkine/RPTPζ-dependent survival pathway.
2011-11-01 | GSE33352 | GEO
Project description:Hematopoietic stem and progenitors cells (HSPCs) are a small population of undifferentiated cells that have the capacity for self-renewal, and differentiate into all blood cell lineages. These cells are the most useful cells for clinical transplantations and for regenerative medicine. So far, it has not been possible to expand adult hematopoietic stem cells (HSCs) without losing their self-renewal properties. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF), and its mRNA is known to be expressed in HSCs. Here, we demonstrate that mice lacking CD74 exhibit an accumulation of hematopoietic stem cells in the BM due to their increased potential to repopulate and compete for BM niches. Our results suggest that CD74 regulates the maintenance of the HSCs and CD18 expression. Its absence leads to induced survival of these cells, and accumulation of quiescent and proliferating cells. Furthermore, in in-vitro experiments, blocking of CD74 elevated the numbers of HSPCs. Thus, we suggest that blocking CD74 could lead to improved clinical insight into bone marrow transplant protocols, enabling improved engraftment.
2021-01-13 | GSE163661 | GEO
Project description:CD74 (invariant chain), expressed on B cells, is directly involved in shaping the B cell repertoire by regulating their survival in health and disease. Binding of its ligand, macrophage migration inhibitory factor (MIF), induces a cascade that results in CD74 intramembrane proteolysis, and the release of the CD74 intracellular domain (CD74-ICD). CD74-ICD translocates to the nucleus where it induces activation of transcription. In the current study, we characterize the transcription regulator activities of CD74 by analysing its ability to alter gene expression in mRNA levels.
2022-11-03 | GSE181675 | GEO