scholarly journals Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells

2018 ◽  
Author(s):  
Yoshiki Higashijima ◽  
Yusuke Matsui ◽  
Teppei Shimamura ◽  
Shuichi Tsutsumi ◽  
Ryo Nakaki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
Leukocyte Adhesion ◽  
List Type ◽  
Chromosome Conformation ◽  
Histone Marks ◽  
Tnf Α ◽  
Simultaneous Inhibition ◽  
Adhesive Interactions

SUMMARYLysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are generally linked to gene repression. However, the functions of repressive histone methylation dynamics during inflammatory responses remain enigmatic. We found that tumor necrosis factor (TNF)-α rapidly induces the co-occupancy of lysine demethylases 7A (KDM7A) and 6A (UTX) with nuclear factor kappa-B (NF-κB) recruited elements in human endothelial cells. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and both are required for activation of NF-κB-dependent inflammatory genes. Chromosome conformation capture-based methods demonstrated increased interactions between TNF-α-induced super enhancers at NF-κB-relevant loci, coinciding with KDM7A- and UTX-recruitment. Simultaneous inhibition of KDM7A and UTX significantly reduced leukocyte adhesion in mice, establishing the biological and potential translational relevance of this mechanism. Collectively, these findings suggest that rapid erasure of repressive histone marks by KDM7A and UTX is essential for NF-κB-dependent regulation of genes that control inflammatory responses of endothelial cells.HIGHLIGHTSKDM7A and UTX cooperatively control NF-κB-dependent transcription in vascular endothelial cells.Demethylation of repressive histone marks by KDM7A and UTX is critical for early inflammatory responses.KDM7A and UTX are associated with TNF-α-induced looping of super enhancers.Pharmacological inhibition of KDM7A and UTX reduces leukocyte adhesive interactions with endothelial cells in mice.

scholarly journals GAS6 Inhibits Granulocyte Adhesion to Endothelial Cells

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2334-2340
Author(s):  
Gian Carlo Avanzi ◽  
Margherita Gallicchio ◽  
Flavia Bottarel ◽  
Loretta Gammaitoni ◽  
Giuliana Cavalloni ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Platelet Activating Factor ◽  
Polymorphonuclear Cells ◽  
Vascular Endothelial ◽  
Tnf Α ◽  
High Concentrations ◽  
Adhesive Interactions ◽  
Factor Α ◽  
Dose Dependent

GAS6 is a ligand for the tyrosine kinase receptors Rse, Axl, and Mer, but its function is poorly understood. Previous studies reported that both GAS6 and Axl are expressed by vascular endothelial cells (EC), which play a key role in leukocyte extravasation into tissues during inflammation through adhesive interactions with these cells. The aim of this work was to evaluate the GAS6 effect on the adhesive function of EC. Treatment of EC with GAS6 significantly inhibited adhesion of polymorphonuclear cells (PMN) induced by phorbol 12-myristate 13-acetate (PMA), platelet-activating factor (PAF), thrombin, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), but not that induced by FMLP and IL-8. GAS6 did not affect adhesion to resting EC. Titration experiments showed that high concentrations of GAS6 were needed to inhibit PMN adhesion and that inhibition was dose-dependent at the concentration range of 0.1 to 1 μg/mL. One possibility was that high concentrations were needed to overwhelm the effect of endogenous GAS6 produced by EC. In line with this possibility, treatment of resting EC with soluble Axl significantly potentiated PMN adhesion. Analysis of localization of GAS6 by confocal microscopy and cytofluorimetric analysis showed that it is concentrated along the plasma membrane in resting EC and treatment with PAF induces depletion and/or redistribution of the molecule. These data suggest that GAS6 functions as a physiologic antiinflammatory agent produced by resting EC and depleted when proinflammatory stimuli turn on the proadhesive machinery of EC.

scholarly journals GAS6 Inhibits Granulocyte Adhesion to Endothelial Cells

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2334-2340 ◽  
Author(s):  
Gian Carlo Avanzi ◽  
Margherita Gallicchio ◽  
Flavia Bottarel ◽  
Loretta Gammaitoni ◽  
Giuliana Cavalloni ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Platelet Activating Factor ◽  
Polymorphonuclear Cells ◽  
Vascular Endothelial ◽  
Tnf Α ◽  
High Concentrations ◽  
Adhesive Interactions ◽  
Factor Α ◽  
Dose Dependent

Abstract GAS6 is a ligand for the tyrosine kinase receptors Rse, Axl, and Mer, but its function is poorly understood. Previous studies reported that both GAS6 and Axl are expressed by vascular endothelial cells (EC), which play a key role in leukocyte extravasation into tissues during inflammation through adhesive interactions with these cells. The aim of this work was to evaluate the GAS6 effect on the adhesive function of EC. Treatment of EC with GAS6 significantly inhibited adhesion of polymorphonuclear cells (PMN) induced by phorbol 12-myristate 13-acetate (PMA), platelet-activating factor (PAF), thrombin, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), but not that induced by FMLP and IL-8. GAS6 did not affect adhesion to resting EC. Titration experiments showed that high concentrations of GAS6 were needed to inhibit PMN adhesion and that inhibition was dose-dependent at the concentration range of 0.1 to 1 μg/mL. One possibility was that high concentrations were needed to overwhelm the effect of endogenous GAS6 produced by EC. In line with this possibility, treatment of resting EC with soluble Axl significantly potentiated PMN adhesion. Analysis of localization of GAS6 by confocal microscopy and cytofluorimetric analysis showed that it is concentrated along the plasma membrane in resting EC and treatment with PAF induces depletion and/or redistribution of the molecule. These data suggest that GAS6 functions as a physiologic antiinflammatory agent produced by resting EC and depleted when proinflammatory stimuli turn on the proadhesive machinery of EC.

scholarly journals TNF-α-Induced YAP/TAZ Activity Mediates Leukocyte-Endothelial Adhesion by Regulating VCAM1 Expression in Endothelial Cells

2018 ◽  
Vol 19 (11) ◽  
pp. 3428 ◽  
Author(s):  
Hyun-Jung Choi ◽  
Na-Eun Kim ◽  
Byeong Kim ◽  
Miran Seo ◽  
Ji Heo
Keyword(s):  
Endothelial Cells ◽  
Rho Gtpases ◽  
Leukocyte Adhesion ◽  
Hippo Pathway ◽  
Specific Inhibitor ◽  
Vascular Diseases ◽  
Adhesive Properties ◽  
Sprouting Angiogenesis ◽  
Tnf Α

YAP/TAZ, a transcriptional co-activator of Hippo pathway, has emerged as a central player in vessel homeostasis such as sprouting angiogenesis and vascular barrier stabilization, during development. However, the role of YAP/TAZ in pathological angiogenesis remains unclear. Here, we demonstrated that YAP/TAZ is a critical mediator in leukocyte-endothelial adhesion induced by the vascular inflammatory cytokine TNF-α. YAP/TAZ was dephosphorylated, translocated from the cytosol to the nucleus, and activated by TNF-α in endothelial cells. A specific inhibitor of Rho GTPases suppressed the TNF-α-induced dephosphorylation of YAP. Knockdown of YAP/TAZ using siRNA significantly reduced the expression of the leukocyte adhesion molecule VCAM1 induced by TNF-α. The adhesion of monocytes to endothelial cells was also markedly reduced by YAP/TAZ silencing. However, knockdown of YAP/TAZ did not affect TNF-α-induced NF-κB signaling. Overall, these results suggest that YAP/TAZ plays critical roles in regulating TNF-α-induced endothelial cell adhesive properties without affecting the NF-κB pathway, and implicate YAP/TAZ as a potential therapeutic target for treating inflammatory vascular diseases.

scholarly journals L-Selectin–Dependent Leukocyte Adhesion to Microvascular But Not to Macrovascular Endothelial Cells of the Human Coronary System

Blood ◽  
1997 ◽  
Vol 89 (9) ◽  
pp. 3228-3235 ◽  
Author(s):  
A. Zakrzewicz ◽  
M. Gräfe ◽  
D. Terbeek ◽  
M. Bongrazio ◽  
W. Auch-Schwelk ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Time Course ◽  
Leukocyte Adhesion ◽  
Flow Chamber ◽  
Shear Stresses ◽  
Selectin Ligands ◽  
Tnf Α ◽  
Factor Α

Abstract To characterize L-selectin–dependent cell adhesion to human vascular endothelium, human cardiac microvascular endothelial cells (HCMEC) and human coronary endothelial cells (HCEC) were isolated from explanted human hearts. The adhesion behavior of human (NALM-6) and mouse (300.19) pre-B cells transfected with cDNA encoding for human L-selectin was compared with that of the respective nontransfected cells in a flow chamber in vitro. More than 80% of the adhesion to tumor necrosis factor-α (TNF-α)–stimulated HCMEC at shear stresses <2 dyne/cm2 was L-selectin dependent and could be equally well blocked by an anti–L-selectin antibody or a L-selectin-IgG-chimera. No L-selectin dependent adhesion to HCEC could be shown. The L-selectin dependent adhesion to HCMEC was insensitive to neuraminidase, but greatly inhibited by addition of NaClO3 , which inhibits posttranslational sulfation and remained elevated for at least 24 hours of stimulation. E-selectin dependent adhesion of HL60 cells to HCMEC was blocked by neuraminidase, but not by NaClO3 and returned to control levels within 18 hours of HCMEC stimulation. It is concluded that microvascular, but not macrovascular endothelial cells express TNF-α–inducible sulfated ligand(s) for L-selectin, which differ from known L-selectin ligands, because sialylation is not required. The prolonged time course of L-selectin dependent adhesion suggests a role in sustained leukocyte recruitment into inflammatory sites in vivo.

Macrophagic Stabilin-1 Restored Disruption of Vascular Integrity Caused by Sepsis

2018 ◽  
Vol 118 (10) ◽  
pp. 1776-1789 ◽  
Author(s):  
Wonhwa Lee ◽  
Seung-Yoon Park ◽  
Youngbum Yoo ◽  
Soon-Young Kim ◽  
Jung-Eun Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Survival Rate ◽  
Vascular Permeability ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
High Mobility ◽  
Neutralizing Antibody ◽  
Dependent Manner ◽  
Vascular Integrity ◽  
In The Wild

AbstractSepsis develops because of overwhelming inflammatory responses to bacterial infection, and disrupts vascular integrity. Stabilin-1 (STAB-1) is a phagocytic receptor, which mediates efferocytosis in a phosphatidylserine (PS)-dependent manner. STAB-1 is expected to play important roles in efferocytosis during sepsis. Here, we determined the role of STAB-1 in maintaining and restoring vascular integrity. Macrophages and vascular endothelial cells were used to assess the effect of STAB-1 on survival rate, phagocytic activity, vascular permeability and transendothelial migration (TEM). Additionally, we investigated whether the high-mobility group box 1 (HMGB1)-receptor for advanced glycated end products complex interfered with the binding of Stab1 to PS. Mortality rate was higher in the Stab1-knockout mice than in the wild-type mice, and STAB-1 deficiency was related to reduced macrophage-mediated efferocytosis and the disruption of vascular integrity, which increased vascular permeability, and enhanced TEM. STAB-1 deficiency promoted lung injury, and elevated the expression of sepsis markers. The exogenous application of the anti-HMGB1 neutralizing antibody improved efferocytosis, vascular integrity and survival rate in sepsis. Collectively, our findings indicated that STAB-1 regulated and maintained vascular integrity through the clearance of infected apoptotic endothelial cells. Moreover, our results suggested that interventions targeting vascular integrity by STAB-1 signalling are promising therapeutic approaches to sepsis.

Abstract 153: Bile Acid Receptor TGR5 Agonism Represents Anti-inflammatory Effects via Stimulating Nitric Oxide Production in Vascular Endothelial Cells

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Taiki Kida ◽  
Yoshiki Tsubosaka ◽  
Masatoshi Hori ◽  
Hiroshi Ozaki ◽  
Takahisa Murata
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Bile Acids ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
Lithocholic Acid ◽  
Signal Pathways ◽  
No Production ◽  
Vascular Endothelial ◽  
Anti Inflammatory

Objective TGR5, a membrane-bound, G-protein-coupled receptor for bile acids, is known to be involved in regulation of energy homeostasis and inflammation. However, little is known about the function of TGR5 in vascular endothelial cells. In the present study, we examined whether TGR5 agonism represents anti-inflammatory effects in vascular endothelial cells focusing on nitric oxide (NO) production. Methods and Results In human umbilical vein endothelial cells (HUVECs), treatment with taurolithocholic acid (TLCA), which has the highest affinity to TGR5 among various bile acids, significantly reduced tumor necrosis factor (TNF)-α-induced vascular cell adhesion molecule (VCAM)-1 protein expression and adhesion of human monocytes, U937. These effects were abrogated by a NO synthase (NOS) inhibitor, N G -Monomethyl-L-arginine (L-NMMA). In bovine aortic endothelial cells (BAECs), treatment with TLCA as well as lithocholic acid, which also has high affinity to TGR5, significantly increased the NO production. In contrast, deoxycholic acid and chenodeoxycholic acid, which possess low affinity to TGR5, did not affect the NO production. Gene depletion of TGR5 by siRNA transfection abolished TLCA-induced NO production in BAECs. TLCA-induced NO production was also observed in HUVECs measured as intracellular cGMP accumulation. We next investigated the signal pathways responsible for the TLCA-induced NO production in endothelial cells. Treatment with TLCA increased endothelial NOS (eNOS) ser1177 phosphorylation in HUVECs. This response was accompanied by increased Akt ser473 phosphorylation and intracellular Ca 2+ ([Ca 2+ ] i ). Treatment with phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, or blockade of calcium channel with La 3+ , significantly decreased TLCA-induced eNOS ser1177 phosphorylation and subsequent NO production. Conclusion These results indicate that TGR5 agonism can mediate anti-inflammatory responses by suppressing VCAM-1 expression and monocytes adhesion to endothelial cells. This function is dependent on NO production via Akt activation and [Ca 2+ ] i increase.

Sign in / Sign up

Export Citation Format

Share Document