Activation of Triggering Receptor Expressed on Myeloid Cells-1 Protects Monocyte from Apoptosis through Regulation of Myeloid Cell Leukemia-1

2013 ◽  
Vol 118 (5) ◽  
pp. 1140-1149 ◽  
Author(s):  
MeiTing Cai ◽  
QiXing Chen ◽  
Chi Chen ◽  
XiWang Liu ◽  
JinChao Hou ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Cell Leukemia ◽  
Proinflammatory Response ◽  
Extracellular Signal Regulated Kinase ◽  
Viral Oncogene ◽  
Extracellular Signal ◽  
Monocyte Apoptosis ◽  
Oncogene Homologue

Abstract Background: Triggering receptor expressed on myeloid cells-1 (TREM-1) can amplify the proinflammatory response and may contribute to the pathogenesis of inflammatory disease such as sepsis. However, the role of TREM-1 in monocyte fate and the detailed molecular mechanisms evoked by TREM-1 are unknown. Methods: Adenoviruses overexpressing TREM-1 were constructed and transfected into a monocytic cell line. After activation of TREM-1 by agonist antibody with or without lipopolysaccharide, apoptosis was induced and assayed using flow cytometry. The signaling pathways downstream of TREM-1 were illustrated by inhibitory experiments. Proapoptotic/antiapoptotic protein levels were measured using immunoblot. In addition, the relationship between the expression levels of TREM-1 in monocytes and the magnitude of monocyte apoptosis were analyzed in septic patients. Results: Activation of TREM-1 protected monocytes from staurosporine-induced apoptosis. This characteristic was also obtained under lipopolysaccharide stimulation. The protection of TREM-1 against monocyte apoptosis was abrogated after inhibition of extracellular signal–regulated kinase or v-akt murine thymoma viral oncogene homologue signaling. Cross-linking of TREM-1 remarkably up-regulated myeloid cell leukemia-1 protein level, and inhibition of extracellular signal–regulated kinase or v-akt murine thymoma viral oncogene homologue resulted in the reduction of myeloid cell leukemia-1 expression. Inhibition of myeloid cell leukemia-1 abolished the antiapoptotic effect of TREM-1. Furthermore, in septic patients, TREM-1 levels were inversely correlated to the magnitude of apoptosis in monocyte. Conclusions: TREM-1 played an important role in apoptosis in monocytes. Activation of TREM-1 protected monocytic cells from apoptosis through activation of both extracellular signal–regulated kinase and v-akt murine thymoma viral oncogene homologue pathways and increased expression of myeloid cell leukemia-1 protein. These findings provide a novel additional mechanism for TREM-1–mediated hyperinflammatory response in monocytes.

scholarly journals Endothelial cell-derived CD95 ligand serves as a chemokine in induction of neutrophil slow rolling and adhesion

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Liang Gao ◽  
Gülce Sila Gülcüler ◽  
Lieke Golbach ◽  
Helena Block ◽  
Alexander Zarbock ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Cecal Ligation ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Flow Chamber ◽  
Integrin Activation ◽  
Cd95 Ligand ◽  
Slow Rolling

Integrin activation is crucial for the regulation of leukocyte rolling, adhesion and trans-vessel migration during inflammation and occurs by engagement of myeloid cells through factors presented by inflamed vessels. However, endothelial-dependent mechanisms of myeloid cell recruitment are not fully understood. Here we show using an autoperfused flow chamber assay of whole blood neutrophils and intravital microscopy of the inflamed cremaster muscle that CD95 mediates leukocyte slow rolling, adhesion and transmigration upon binding of CD95-ligand (CD95L) that is presented by endothelial cells. In myeloid cells, CD95 triggers activation of Syk-Btk/PLCγ2/Rap1 signaling that ultimately leads to integrin activation. Excitingly, CD95-deficient myeloid cells exhibit impaired bacterial clearance in an animal model of sepsis induced by cecal ligation and puncture (CLP). Our data identify the cellular and molecular mechanisms underlying the chemoattractant effect of endothelial cell-derived CD95L in induction of neutrophil recruitment and support the use of therapeutic inhibition of CD95’s activity in inflammatory diseases.

scholarly journals C/EBPα initiates primitive myelopoiesis in pluripotent embryonic cells

Blood ◽  
2009 ◽  
Vol 114 (1) ◽  
pp. 40-48 ◽  
Author(s):  
Yaoyao Chen ◽  
Ricardo M. B. Costa ◽  
Nick R. Love ◽  
Ximena Soto ◽  
Martin Roth ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Embryonic Cells ◽  
Single Factor ◽  
Pluripotent Cells ◽  
Highly Active ◽  
Vertebrate Embryos ◽  
Necessary And Sufficient

Abstract The molecular mechanisms that underlie the development of primitive myeloid cells in vertebrate embryos are not well understood. Here we characterize the role of cebpa during primitive myeloid cell development in Xenopus. We show that cebpa is one of the first known hematopoietic genes expressed in the embryo. Loss- and gain-of-function studies show that it is both necessary and sufficient for the development of functional myeloid cells. In addition, we show that cebpa misexpression leads to the precocious induction of myeloid cell markers in pluripotent prospective ectodermal cells, without the cells transitioning through a general mesodermal state. Finally, we use live imaging to show that cebpa-expressing cells exhibit many attributes of terminally differentiated myeloid cells, such as highly active migratory behavior, the ability to quickly and efficiently migrate toward wounds and phagocytose bacteria, and the ability to enter the circulation. Thus, C/EPBα is the first known single factor capable of initiating an entire myelopoiesis pathway in pluripotent cells in the embryo.

scholarly journals Periplaneta americana Extracts Promote Skin Wound Healing via Nuclear Factor Kappa B Canonical Pathway and Extracellular Signal-Regulated Kinase Signaling

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Qin Song ◽  
Qiheng Gou ◽  
Yuxin Xie ◽  
Zhen Zhang ◽  
Chaomei Fu
Keyword(s):  
Wound Healing ◽  
Molecular Mechanisms ◽  
Periplaneta Americana ◽  
Nuclear Factor Kappa B ◽  
Nuclear Translocation ◽  
Nuclear Factor ◽  
Protective Function ◽  
Extracellular Signal Regulated Kinase ◽  
Nuclear Factor Kappa ◽  
Extracellular Signal

Periplaneta americana extracts (PAEs) exhibit wound healing properties. However, the underlying molecular mechanisms are not well understood. Here, we treated human skin fibroblasts (HSF) with PAE and the proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The wound healing and transwell migration assays were used to detect cell migration. Nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) pathways were analyzed by Western blot (WB). Immunofluorescence staining was used to detect the key molecular localization in the cells. The results showed that PAE enhanced the proliferation and migration of HSF cells. The expression and activation of key proteins such as RelA and p-ERK were increased in NF-κB and ERK pathways followed by nuclear translocation. In vivo, both WB and immunohistochemical (IHC) staining showed that PAE enhanced p-IκBα and p-ERK activation and the nuclear translocation of RelA. Our study suggests that the protective function of PAE is mediated via enhanced NF-κB and ERK signaling.

scholarly journals Heavy Metals in the Environment and Thyroid Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4052
Author(s):  
Fiorenza Gianì ◽  
Roberta Masto ◽  
Maria Antonietta Trovato ◽  
Pasqualino Malandrino ◽  
Marco Russo ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Thyroid Cancer ◽  
Molecular Mechanisms ◽  
Human Thyroid ◽  
Thyroid Cells ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Low Levels ◽  
Causative Link

In recent decades, the incidence of thyroid cancer has increased more than most other cancers, paralleling the generalized worldwide increase in metal pollution. This review provides an overview of the evidence supporting a possible causative link between the increase in heavy metals in the environment and thyroid cancer. The major novelty is that human thyroid stem/progenitor cells (thyrospheres) chronically exposed to different metals at slightly increased environmentally relevant concentrations show a biphasic increase in proliferation typical of hormesis. The molecular mechanisms include, for all metals investigated, the activation of the extracellular signal-regulated kinase (ERK1/2) pathway. A metal mixture, at the same concentration of individual metals, was more effective. Under the same conditions, mature thyrocytes were unaffected. Preliminary data with tungsten indicate that, after chronic exposure, additional abnormalities may occur and persist in thyrocytes derived from exposed thyrospheres, leading to a progeny population of transformation-prone thyroid cells. In a rat model predisposed to develop thyroid cancer, long-term exposure to low levels of metals accelerated and worsened histological signs of malignancy in the thyroid. These studies provide new insight on metal toxicity and carcinogenicity occurring in thyroid cells at a low stage of differentiation when chronically exposed to metal concentrations that are slightly increased, albeit still in the “normal” range.

scholarly journals Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML

Blood ◽  
2021 ◽  
Author(s):  
Margaux Sevin ◽  
Franck Debeurme ◽  
Lucie Laplane ◽  
Severine Badel ◽  
Margot Morabito ◽  
...  
Keyword(s):  
Myeloid Cell ◽  
Methylation Pattern ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Molecule Inhibitor ◽  
Mitogen Activated Protein ◽  
Monocyte Apoptosis ◽  
Combined Strategy

Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that, in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to MCL1 (myeloid cell leukemia-1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point also to the implication of the MAPK (mitogen-activated protein kinase) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine CYTL1 (Cytokine-like protein 1) promotes ERK (extracellular signal-regulated kinase) activation through CCR2 (C-C chemokine receptor type 2). Combined MAPK and MCL1 inhibition restores apoptosis of CMML patient monocytes and reduces the expansion of patient-derived xenografts in mice. These results designate the combined inhibition of MCL1 and MAPK as a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.

Retinoic acid–induced cell cycle arrest of human myeloid cell lines is associated with sequential down-regulation of c-Myc and cyclin E and posttranscriptional up-regulation of p27Kip1

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 2199-2206 ◽  
Author(s):  
Anna Dimberg ◽  
Fuad Bahram ◽  
Inger Karlberg ◽  
Lars-Gunnar Larsson ◽  
Kenneth Nilsson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
Cell Cycle Arrest ◽  
Molecular Mechanisms ◽  
Cyclin E ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
G1 Arrest ◽  
Down Regulation ◽  
Cycle Arrest

Abstract All-trans retinoic acid (ATRA) is a potential therapeutic agent for the treatment of hematopoietic malignancies, because of its function as an inducer of terminal differentiation of leukemic blasts. Although the efficacy of ATRA as an anticancer drug has been demonstrated by the successful treatment of acute promyelocytic leukemia (APL), the molecular mechanisms of ATRA-induced cell cycle arrest of myeloid cells have not been fully investigated. In this study, we show that the onset of ATRA-induced G0/G1 arrest of human monoblastic U-937 cells is linked to a sharp down-regulation of c-Myc and cyclin E levels and an increase in p21WAF1/CIP1 expression. This is followed by an increase in p27Kip1 protein expression due to enhanced protein stability. The importance of an early decrease in Myc expression for these events was demonstrated by the failure of a U-937 subline with constitutive exogenous expression of v-Myc to cell cycle arrest and regulate cyclin E and p27Kip1 in response to ATRA. Preceding the initiation of G1 arrest, a transient rise in retinoblastoma protein (pRb), p107, and cyclin A levels was detected. Later, a rapid fall in the levels of cyclins A and B and a coordinate dephosphorylation of pRb at Ser780, Ser795, and Ser807/811 coincided with the accumulation of cells in G1. These results thus identify a decrease in c-Myc and cyclin E levels and a posttranscriptional up-regulation of p27Kip1 as important early changes, and position them in the complex chain of events regulating ATRA-induced cell cycle arrest of myeloid cells.

scholarly journals Triiodothyronine utilizes phosphatidylinositol 3-kinase pathway to activate anti-apoptotic myeloid cell leukemia-1

2008 ◽  
Vol 41 (3) ◽  
pp. 177-186 ◽  
Author(s):  
Maciej Pietrzak ◽  
Monika Puzianowska-Kuznicka
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Cell Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Hek 293 ◽  
Phosphatidylinositol 3

Triiodothyronine (T3) regulates apoptosis in cells according to their developmental stage, cell type, and pathophysiological state. The molecular mechanisms of this regulation, however, have been largely unknown. In this work, we show that the expression of the myeloid cell leukemia-1 (MCL-1) protein, an anti-apoptotic member of B-cell lymphoma-2 (BCL-2) family, increases in thyroid hormone receptor-expressing human kidney-2 (HK2) cells upon 6-h incubation in 100 nM T3; we also describe the molecular mechanisms leading to this phenomenon. Transcription regulation assays performed in human embryonic kidney (HEK) 293 cells show that 100 nM T3 increases transcription from the MCL-1 promoter twofold in the presence of thyroid hormone receptor β1, but not of its α1 isoform. However, this increase is not a result of direct activation via the thyroid hormone-response element, TRE-DR4, located at the −998 to −983 position in this promoter; furthermore, the presence of 9-cis-retinoic acid receptor is not required. The promoter's activation is abolished in the presence of phosphatidylinositol 3-kinase (PI3-K) inhibitor, wortmannin. The −295 to −107 promoter fragment contains all sequences involved in T3-dependent activation of the MCL-1 promoter, and cAMP-responsive element located at the −262 to −255 position is a major mediator in this process. Therefore, MCL-1 expression is activated by T3, which increases its promoter activity by a non-genomic mechanism using the PI3-K signal transduction pathway. We propose that this is another mechanism by which T3 regulates apoptosis.

scholarly journals Neuroprotective Effects of B-Type Cinnamon Procyanidin Oligomers on MPP+-Induced Apoptosis in a Cell Culture Model of Parkinson’s Disease

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6422
Author(s):  
Qi Xu ◽  
Ziyu Chen ◽  
Borong Zhu ◽  
Yiming Li ◽  
Manju B. Reddy ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Water Soluble ◽  
Cell Culture Model ◽  
Neuroprotective Effects ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Culture Model ◽  
A Cell ◽  
Induced Apoptosis ◽  
Soluble Components

Cinnamon procyanidin oligomers (CPOs) are water-soluble components extracted from cinnamon. This study aims to explore the neuroprotection of B-type CPO (CPO-B) against 1-methyl-4-phenylpyridinium (MPP+)-mediated cytotoxicity and the molecular mechanisms underlying its protection. The results demonstrated that CPO-B showed protection by increasing cell viability, attenuating an intracellular level of reactive oxygen species, downregulating cleaved caspase-3 expression, and upregulating the Bcl-2/Bax ratio. Moreover, CPO-B completely blocked the dephosphorylation of extracellular, signal-regulated kinase 1 and 2 (Erk1/2) caused by MPP+. Treatment with an Erk1/2 inhibitor, SCH772984, significantly abolished the neuroprotection of CPO-B against MPP+. Taken together, we demonstrate that CPO-B from cinnamon bark provided protection against MPP+ in cultured SH-SY5Y cells, and the potential mechanisms may be attributed to its ability to modulate the dysregulation between pro-apoptotic and anti-apoptotic proteins through the Erk1/2 signaling pathway. Our findings suggest that the addition of cinnamon to food or supplements might benefit patients with PD.

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