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CSF-1 signaling mediates recovery from acute kidney injury.
Zhang MZ, Yao B, Yang S, Jiang L, Wang S, Fan X, Yin H, Wong K, Miyazawa T, Chen J, Chang I, Singh A, Harris RC
(2012) J Clin Invest 122: 4519-32
MeSH Terms: Acute Kidney Injury, Animals, Cell Differentiation, Cell Polarity, Cell Proliferation, Cells, Cultured, Dendritic Cells, Diphtheria Toxin, Kidney, Kidney Tubules, Proximal, Macrophage Colony-Stimulating Factor, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptor, Macrophage Colony-Stimulating Factor, Recombinant Fusion Proteins, Recovery of Function, Regeneration, Signal Transduction
Show Abstract · Added February 26, 2014
Renal tubule epithelia represent the primary site of damage in acute kidney injury (AKI), a process initiated and propagated by the infiltration of macrophages. Here we investigated the role of resident renal macrophages and dendritic cells in recovery from AKI after ischemia/reperfusion (I/R) injury or a novel diphtheria toxin-induced (DT-induced) model of selective proximal tubule injury in mice. DT-induced AKI was characterized by marked renal proximal tubular cell apoptosis. In both models, macrophage/dendritic cell depletion during the recovery phase increased functional and histologic injury and delayed regeneration. After I/R-induced AKI, there was an early increase in renal macrophages derived from circulating inflammatory (M1) monocytes, followed by accumulation of renal macrophages/dendritic cells with a wound-healing (M2) phenotype. In contrast, DT-induced AKI only generated an increase in M2 cells. In both models, increases in M2 cells resulted largely from in situ proliferation in the kidney. Genetic or pharmacologic inhibition of macrophage colony-stimulating factor (CSF-1) signaling blocked macrophage/dendritic cell proliferation, decreased M2 polarization, and inhibited recovery. These findings demonstrated that CSF-1-mediated expansion and polarization of resident renal macrophages/dendritic cells is an important mechanism mediating renal tubule epithelial regeneration after AKI.
2 Communities
3 Members
0 Resources
21 MeSH Terms
Prostaglandin E2 restrains macrophage maturation via E prostanoid receptor 2/protein kinase A signaling.
Zaslona Z, Serezani CH, Okunishi K, Aronoff DM, Peters-Golden M
(2012) Blood 119: 2358-67
MeSH Terms: Animals, Antigens, Differentiation, CD11b Antigen, Cell Line, Tumor, Cells, Cultured, Cyclic AMP-Dependent Protein Kinases, Dinoprostone, Female, Flow Cytometry, Gene Expression, Macrophage Colony-Stimulating Factor, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Misoprostol, Peritonitis, Prostaglandin Antagonists, Receptor, Macrophage Colony-Stimulating Factor, Receptors, Prostaglandin E, EP2 Subtype, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Thioglycolates, Xanthones
Show Abstract · Added May 4, 2017
Prostaglandin E(2) (PGE(2)) is a lipid mediator that acts by ligating 4 distinct G protein-coupled receptors, E prostanoid (EP) 1 to 4. Previous studies identified the importance of PGE(2) in regulating macrophage functions, but little is known about its effect on macrophage maturation. Macrophage maturation was studied in vitro in bone marrow cell cultures, and in vivo in a model of peritonitis. EP2 was the most abundant PGE(2) receptor expressed by bone marrow cells, and its expression further increased during macrophage maturation. EP2-deficient (EP2(-/-)) macrophages exhibited enhanced in vitro maturation compared with wild-type cells, as evidenced by higher F4/80 expression. An EP2 antagonist also increased maturation. In the peritonitis model, EP2(-/-) mice exhibited a higher percentage of F4/80(high)/CD11b(high) cells and greater expression of macrophage colony-stimulating factor receptor (M-CSFR) in both the blood and the peritoneal cavity. Subcutaneous injection of the PGE(2) analog misoprostol decreased M-CSFR expression in bone marrow cells and reduced the number of peritoneal macrophages in wild-type mice but not EP2(-/-) mice. The suppressive effect of EP2 ligation on in vitro macrophage maturation was mimicked by a selective protein kinase A agonist. Our findings reveal a novel role for PGE(2)/EP2/protein kinase A signaling in the suppression of macrophage maturation.
0 Communities
1 Members
0 Resources
25 MeSH Terms
Granulocyte-macrophage colony-stimulating factor regulates effector differentiation of invariant natural killer T cells during thymic ontogeny.
Bezbradica JS, Gordy LE, Stanic AK, Dragovic S, Hill T, Hawiger J, Unutmaz D, Van Kaer L, Joyce S
(2006) Immunity 25: 487-97
MeSH Terms: Animals, Cell Differentiation, Cells, Cultured, Cytokines, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Killer Cells, Natural, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Receptor, Macrophage Colony-Stimulating Factor, T-Lymphocyte Subsets, Thymus Gland
Show Abstract · Added December 10, 2013
Invariant natural killer T (iNKT) cell-derived cytokines have important functions in inflammation, host defense, and immunoregulation. Yet, when and how iNKT cells undergo effector differentiation, which endows them with the capacity to rapidly secrete cytokines upon activation, remains unknown. We discovered that granulocyte-macrophage colony-stimulating factor (Csf-2)-deficient mice developed iNKT cells that failed to respond to the model antigen alpha-galactosylceramide because of an intrinsic defect in the fusion of secretory vesicles with the plasma membrane. Exogenous Csf-2 corrected the functional defect only when supplied during the development of thymic, but not mature, splenic Csf-2-deficient iNKT cells. Thus, we ascribe a unique function to Csf-2, which regulates iNKT cell effector differentiation during development by a mechanism that renders them competent for cytokine secretion.
0 Communities
3 Members
0 Resources
15 MeSH Terms
Multiple functional domains of AML1: PU.1 and C/EBPalpha synergize with different regions of AML1.
Petrovick MS, Hiebert SW, Friedman AD, Hetherington CJ, Tenen DG, Zhang DE
(1998) Mol Cell Biol 18: 3915-25
MeSH Terms: Animals, Binding Sites, CCAAT-Enhancer-Binding Proteins, COS Cells, Cell Line, Chlorocebus aethiops, Core Binding Factor Alpha 2 Subunit, DNA, DNA-Binding Proteins, HeLa Cells, Humans, Mutagenesis, Nuclear Proteins, Phosphorylation, Promoter Regions, Genetic, Proto-Oncogene Proteins, Receptor, Macrophage Colony-Stimulating Factor, Trans-Activators, Transcription Factors, Transcriptional Activation
Show Abstract · Added June 10, 2010
Control elements of many genes are regulated by multiple activators working in concert to confer the maximal level of expression, but the mechanism of such synergy is not completely understood. The promoter of the human macrophage colony-stimulating factor (M-CSF) receptor presents an excellent model with which we can study synergistic, tissue-specific activation for two reasons. First, myeloid-specific expression of the M-CSF receptor is regulated transcriptionally by three factors which are crucial for normal hematopoiesis: PU.1, AML1, and C/EBPalpha. Second, these proteins interact in such a way as to demonstrate at least two examples of synergistic activation. We have shown that AML1 and C/EBPalpha activate the M-CSF receptor promoter in a synergistic manner. As we report here, AML1 also synergizes, and interacts physically, with PU. 1. Detailed analysis of the physical and functional interaction of AML1 with PU.1 and C/EBPalpha has revealed that the proteins contact one another through their DNA-binding domains and that AML1 exhibits cooperative DNA binding with C/EBPalpha but not with PU.1. This difference in DNA-binding abilities may explain, in part, the differences observed in synergistic activation. Furthermore, the activation domains of all three factors are required for synergistic activation, and the region of AML1 required for synergy with PU.1 is distinct from that required for synergy with C/EBPalpha. These observations present the possibility that synergistic activation is mediated by secondary proteins contacted through the activation domains of AML1, C/EBPalpha, and PU.1.
1 Communities
1 Members
0 Resources
20 MeSH Terms
Synergistic up-regulation of the myeloid-specific promoter for the macrophage colony-stimulating factor receptor by AML1 and the t(8;21) fusion protein may contribute to leukemogenesis.
Rhoades KL, Hetherington CJ, Rowley JD, Hiebert SW, Nucifora G, Tenen DG, Zhang DE
(1996) Proc Natl Acad Sci U S A 93: 11895-900
MeSH Terms: Animals, Bone Marrow, Cell Line, Chlorocebus aethiops, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Core Binding Factor Alpha 2 Subunit, DNA Primers, DNA-Binding Proteins, Humans, Leukemia, Myeloid, Acute, Organ Specificity, Polymerase Chain Reaction, Promoter Regions, Genetic, Proto-Oncogene Proteins, RUNX1 Translocation Partner 1 Protein, Receptor, Macrophage Colony-Stimulating Factor, Transcription Factors, Translocation, Genetic, Tumor Cells, Cultured, Up-Regulation
Show Abstract · Added June 10, 2010
AML1 is involved in the (8;21) translocation, associated with acute myelogenous leukemia (AML)-type M2, which results in the production of the AML1-ETO fusion protein: the amino-terminal 177 amino acids of AML1 and the carboxyl-terminal 575 amino acids of ETO. The mechanism by which AML1-ETO accomplishes leukemic transformation is unknown; however, AML1-ETO interferes with AML1 transactivation of such AML1 targets as the T-cell receptor beta enhancer and the granulocyte-macrophage colony-stimulating factor promoter. Herein, we explored the effect of AML1-ETO on regulation of a myeloid-specific AML1 target, the macrophage colony-stimulating factor (M-CSF) receptor promoter. We found that AML1-ETO and AML1 work synergistically to transactivate the M-CSF receptor promoter, thus exhibiting a different activity than previously described. Truncation mutants within the ETO portion of AML1-ETO revealed the region of ETO necessary for the cooperativity between AML1 and AML1-ETO lies between amino acids 347 and 540. Endogenous M-CSF receptor expression was examined in Kasumi-1 cells, derived from a patient with AML-M2 t(8;21) and the promonocytic cell line U937. Kasumi-1 cells exhibited a significantly higher level of M-CSF receptor expression than U937 cells. Bone marrow from patients with AML-M2 t(8;21) also exhibited a higher level of expression of M-CSF receptor compared with normal controls. The upregulation of M-CSF receptor expression by AML1-ETO may contribute to the development of a leukemic state in these patients.
1 Communities
1 Members
0 Resources
21 MeSH Terms
CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter.
Zhang DE, Hetherington CJ, Meyers S, Rhoades KL, Larson CJ, Chen HM, Hiebert SW, Tenen DG
(1996) Mol Cell Biol 16: 1231-40
MeSH Terms: Animals, Base Sequence, CCAAT-Enhancer-Binding Proteins, Cell Line, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Humans, Molecular Sequence Data, Monocytes, Neoplasm Proteins, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Receptor, Macrophage Colony-Stimulating Factor, Signal Transduction, Transcription Factors
Show Abstract · Added June 10, 2010
Transcription factors play a key role in the development and differentiation of specific lineages from multipotential progenitors. Identification of these regulators and determining the mechanism of how they activate their target genes are important for understanding normal development of monocytes and macrophages and the pathogenesis of a common form of adult acute leukemia, in which the differentiation of monocytic cells is blocked. Our previous work has shown that the monocyte-specific expression of the macrophage colony-stimulating factor (M-CSF) receptor is regulated by three transcription factors interacting with critical regions of the M-CSF receptor promoter, including PU.1 and AML1.PU.1 is essential for myeloid cell development, while the AML1 gene is involved in several common leukemia-related chromosome translocations, although its role in hematopoiesis has not been fully identified. Along with AML1, a third factor, Mono A, interacts with a small region of the promoter which can function as a monocyte-specific enhancer when multimerized and linked to a heterologous basal promoter. Here, we demonstrate by electrophoretic mobility shift assays with monocytic nuclear extracts, COS-7 cell-transfected factors, and specific antibodies that the monocyte-enriched factor Mono A is CCAAT enhancer-binding protein (C/EBP). C/EBP has been shown previously to be an important transcription factor involved in hepatocyte and adipocyte differentiation; in hematopoietic cells, C/EBP is specifically expressed in myeloid cells. In vitro binding analysis reveals a physical interaction between C/EBP and AML1. Further transfection studies show that C/EBP and AML1 in concert with the AML1 heterodimer partner CBF beta synergistically activate M-CSF receptor by more then 60 fold. These results demonstrate that C/EBP and AML1 are important factors for regulating a critical hematopoietic growth factor receptor, the M-CSF receptor, suggesting a mechanism of how the AML1 fusion protein could contribute to acute myeloid leukemia. Furthermore, they demonstrate physical and functional interactions between AML1 and C/EBP transcription factor family members.
1 Communities
1 Members
0 Resources
17 MeSH Terms
Rearrangement of the AML1/CBFA2 gene in myeloid leukemia with the 3;21 translocation: expression of co-existing multiple chimeric genes with similar functions as transcriptional repressors, but with opposite tumorigenic properties.
Zent C, Kim N, Hiebert S, Zhang DE, Tenen DG, Rowley JD, Nucifora G
(1996) Curr Top Microbiol Immunol 211: 243-52
MeSH Terms: Animals, Cell Line, Chromosomes, Human, Pair 3, Cloning, Molecular, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Gene Rearrangement, Humans, Leukemia, Myeloid, MDS1 and EVI1 Complex Locus Protein, Mice, Mice, Nude, Neoplasm Proteins, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogenes, RNA-Binding Proteins, Rats, Receptor, Macrophage Colony-Stimulating Factor, Ribosomal Proteins, Transcription Factors, Transfection, Translocation, Genetic
Show Abstract · Added June 10, 2010
Several recurring chromosomal translocations involve the AML1 gene at 21q22 in myeloid leukemias resulting in fusion mRNAs and chimeric proteins between AML1 and a gene on the partner chromosome. AML1 corresponds to CBFA2, one of the DNA-binding subunits of the enhancer core binding factor CBF. Other CBF DNA-binding subunits are CBFA1 and CBFA3, also known as AML3 and AML2. AML1, AML2 and AML3 are each characterized by a conserved domain at the amino end, the runt domain, that is necessary for DNA-binding and protein dimerization, and by a transactivation domain at the carboxyl end. AML1 was first identified as the gene located at the breakpoint junction of the 8;21 translocation associated with acute myeloid leukemia. The t(8;21)(q22;q22) interrupts AML1 after the runt homology domain, and fuses the 5' part of AML1 to almost all of ETO, the partner gene on chromosome 8. AML1 is an activator of several myeloid promoters; however, the chimeric AML1/ETO is a strong repressor of some AML1-dependent promoters. AML1 is also involved in the t(3;21)(q26;q22), that occurs in myeloid leukemias primarily following treatment with topoisomerase II inhibitors. We have studied five patients with a 3;21 translocation. In all cases, AML1 is interrupted after the runt domain, and is translocated to chromosome band 3q26. As a result of the t(3;21), AML1 is consistently fused to two separate genes located at 3q26. The two genes are EAP, which codes for the abundant ribosomal protein L22, and MDS1, which encodes a small polypeptide of unknown function. In one of our patients, a third gene EVI1 is also involved. EAP is the closest to the breakpoint junction with AML1, and EVI1 is the furthest away. The fusion of EAP to AML1 is not in frame, and leads to a protein that is terminated shortly after the fusion junction by introduction of a stop codon. The fusion of AML1 to MDS1 is in frame, and adds 127 codons to the interrupted AML1. Thus, in the five cases that we studied, the 3;21 translocation results in expression of two coexisting chimeric mRNAs which contain the identical runt domain at the 5' region, but differ in the 3' region. In addition, the chimeric transcript AML1/MDS1/EVI1 has also been detected in cells from one patient with the 3;21 translocation as well as in one of our patients. Several genes necessary for myeloid lineage differentiation contain the target sequence for AML1 in their regulatory regions. One of them is the CSF1R gene. We have compared the normal AML1 to AML1/MDS1, AML1/EAP and AML1/MDS1/EVI1 as transcriptional regulators of the CSF1R promoter. Our results indicate that AML1 can activate the promoter, and that the chimeric proteins compete with the normal AML1 and repress expression from the CSF1R promoter. AML1/MDS1 and AML1/EAP affect cell growth and phenotype when expressed in rat fibroblasts. However, the pattern of tumor growth of cells expressing the different chimeric genes in nude mice is different. We show that when either fusion gene is expressed, the cells lose contact inhibition and form foci over the monolayer. In addition, cells expressing AML1/MDS1 grow larger tumors in nude mice, whereas cells expressing only AML1/EAP do not form tumors, and cells expressing both chimeric genes induce tumors of intermediate size. Thus, although both chimeric genes have similar effects in transactivation assays of the CSF1R promoter, they affect cell growth differently in culture and have opposite effects as tumor promoters in vivo. Because of the results obtained with cells expressing one or both genes, we conclude that MDS1 seems to have tumorigenic properties, but that AML1/EAP seems to repress the oncogenic property of AML1/MDS1.
1 Communities
1 Members
0 Resources
24 MeSH Terms