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Inhibition of VCAM-1 expression by CORM-3: the role of the ubiquitin proteasome system, p38 and mitochondrial respiration

ABSTRACT: Carbon monoxide (CO) abrogates TNF-alpha mediated inflammatory responses in endothelial cells, yet, the underlying mechanism hereof is still elusive. We sought to explore potential mechanisms by which CO down-regulates VCAM-1 expression on TNF-alpha stimulated human umbilical vein endothelial cells (HUVEC). By genome-wide gene expression profiling and pathway analysis we studied the relevance of particular pathways for the anti-inflammatory effect of CO. In CO-releasing molecules-3 (CORM-3) stimulated HUVEC, significant changes in gene expression were found for genes implicated in the proteasome and porphyrine pathways. Although proteasome activities were increased by CORM-3, proteasome inhibitors did not abolish CORM-3‘s effect. Likewise, HO-1 inhibitors did not abrogate the ability of CORM-3 to down-regulate VCAM-1 expression. MAPK p38 was inhibited by CORM-3. Accordingly, VCAM-1 expression was down-regulated by the p38 inhibitor SB203580. Down-regulation of VCAM-1 by CORM-3 only occurred at concentrations that partly inhibit ATP production. Sodium azide and oligomycin paralleled the effect of CORM-3 in this regard. In conclusion, down-regulation of VCAM-1 by CORM-3 seems to be mediated via inhibition of p38 and mitochondrial respiration. Although CORM-3 up-regulates several genes in the ubiquitin proteasome sytem (UPS) or porphyrin pathway, there is no evidence that these changes are involved in the anti-inflammatory properties of CORM-3.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22175 | GEO | 2011/07/11

SECONDARY ACCESSION(S): PRJNA127685

REPOSITORIES: GEO

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Inhibition of VCAM-1 expression by CORM-3: the role of the ubiquitin proteasome system, p38 and mitochondrial respiration

Project description:Carbon monoxide (CO) abrogates TNF-alpha mediated inflammatory responses in endothelial cells, yet, the underlying mechanism hereof is still elusive. We sought to explore potential mechanisms by which CO down-regulates VCAM-1 expression on TNF-alpha stimulated human umbilical vein endothelial cells (HUVEC). By genome-wide gene expression profiling and pathway analysis we studied the relevance of particular pathways for the anti-inflammatory effect of CO. In CO-releasing molecules-3 (CORM-3) stimulated HUVEC, significant changes in gene expression were found for genes implicated in the proteasome and porphyrine pathways. Although proteasome activities were increased by CORM-3, proteasome inhibitors did not abolish CORM-3‘s effect. Likewise, HO-1 inhibitors did not abrogate the ability of CORM-3 to down-regulate VCAM-1 expression. MAPK p38 was inhibited by CORM-3. Accordingly, VCAM-1 expression was down-regulated by the p38 inhibitor SB203580. Down-regulation of VCAM-1 by CORM-3 only occurred at concentrations that partly inhibit ATP production. Sodium azide and oligomycin paralleled the effect of CORM-3 in this regard. In conclusion, down-regulation of VCAM-1 by CORM-3 seems to be mediated via inhibition of p38 and mitochondrial respiration. Although CORM-3 up-regulates several genes in the ubiquitin proteasome sytem (UPS) or porphyrin pathway, there is no evidence that these changes are involved in the anti-inflammatory properties of CORM-3. In this study we focused on the potential of CORM-3 to downregulate the expression of TNF-alpha mediated inflammataroy genes

2011-07-11 | E-GEOD-22175 | biostudies-arrayexpress

Homo sapiens

Project description:Inhibition of VCAM-1 expression by CORM-3: the role of the ubiquitin proteasome system, p38 and mitochondrial respiration

| PRJNA127685 | ENA

IL-4 mediated gene expression profiles in vascular endothelial cells

Project description:Endothelial cell activation and dysfunction underlie many vascular disorders, including atherosclerosis and inflammation. Here, we show that interleukin (IL)-4 markedly induced vascular cell adhesion molecule (VCAM)-1, both in cultured endothelial cells and in the intact endothelium in mice. Combined treatment with IL-4 and tumor necrosis factor (TNF)- alpha resulted in further, sustained induction of VCAM-1 expression. IL-4-mediated induction of VCAM-1 and secondary monocyte adhesion was predominantly regulated by the transcription factor, STAT6. Genome-wide survey of IL-4-mediated STAT6 binding from sequential chromatin-immunoprecipitation with deep-sequencing (ChIP-seq) in endothelial cells revealed regions of transient and sustained transcription factor binding. By combining DNA microarrays and ChIP-seq at the same time points, the majority of IL-4-responsive genes were shown to be STAT6-dependent and associated with direct STAT6 binding to their promoter. IL-4-mediated stable binding of STAT6 led to sustained target gene expression. Moreover, our strategy led to the identification of a novel functionally important STAT6 binding site within -16 kb upstream of the VCAM-1 gene. Taken together, these findings support a critical role for STAT6 in mediating IL-4 signal transduction in endothelial cells. Identification of a novel IL-4-mediated VCAM-1 enhancer may provide a foundation for targeted therapy in vascular disease (ChIP-seq data not submitted to GEO). Total 13 samples were derived from [1] HUVEC treated in the absence (0h) or presence of IL-4 (1,2,4,8, and 16h) to determine IL-4 regulated gene in endotherial cells, [2] control-siRNA or si-STAT6 transfected HUVEC cells treated in the absence or presenceof IL-4 [3] Ad-control or Ad-CA-STAT6 transfected HUVEC cells for the identification of STAT-6 dependent genes in endothelial cells.

2011-05-01 | E-GEOD-28117 | biostudies-arrayexpress

VCAM-1 mediates proximal tubule-immune cell cross talk in failed tubule recovery during AKI-to-CKD transition

Project description:Studies in animal models have suggested a linkage between the inflammatory response to injury and subsequent nephron loss during the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Failure of normal repair during the CKD transition correlates with de novo expression of vascular cell adhesion protein-1 (VCAM-1) by a subset of injured proximal tubule cells. This study identified the role of VCAM-1 expression in promoting the failed repair state. Single-cell transcriptome analysis of patients with AKI and CKD and whole kidney RNA and protein analyses of mouse models of CKD confirmed a marked increase of VCAM-1 expression in the proximal tubules of injured kidneys. In immortalized mouse proximal tubular cells and primary cultured renal cells (PCRCs), VCAM-1 expression was induced by proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Analyses of bulk RNA sequencing of TNF-α-treated primary cultured renal cells or pseudo-bulk RNA sequencing of biopsies from Kidney Precision Medicine Project datasets indicated activation of NF-κB and an enrichment of inflammatory response and cell adhesion pathways in VCAM-1-positive cells. Pharmacological inhibition of NF-κB signaling or genetic deletion of myeloid differentiation factor 88 and TIR domain-containing adapter-inducing interferon-β suppressed TNF-α- and IL-1β-induced VCAM-1 expression in vitro. TNF-α stimulation or overexpression of VCAM-1 significantly increased splenocyte adhesion to the mouse proximal tubular monolayer in culture. These results demonstrate that persistence of proinflammatory cytokines after AKI can induce NF-κB-dependent VCAM-1 expression by proximal tubule cells, mediating increased immune cell adhesion to the tubule and thus promoting further tubule injury and greater risk of progression from AKI to CKD.

2024-09-03 | GSE254359 | GEO

Transcription profiling of Homo Sapiens Human Umbilical Endothelial Cells normal vs treated with TNF to investigate effect of TNF-alpha on microRNAs levels

Project description:Effect of TNF-alpha on microRNAs levels in Human Umbilical Endothelial Cells (HUVECs). HUVEC that were treated or not for 2 or 24 hours with TNF (10 ng/ml). Duplicate samples (1 or 2) of two different isolations of HUVEC (A or B)

2009-12-01 | E-MTAB-150 | biostudies-arrayexpress

Epression Data from HUVEC and HUAEC

Project description:To assess if HUVEC and HUAEC differ in suscptibility to inflammation and inflammation resolution, the cells were stimulated for 24 hrs with TNF followed by RNA isolation. Two additional groups were first stimulated with TNF (24 hr) followed by TNF removal (12 and 24 hrs). Expression profiles were compared to basal conditions, i.e. cells cultured in normal medium We used micro-arrays to assess if Gene-xpression profiles between HUVEC and HUAEC differ under inflammatory conditions and under conditions of inflammation resolution

2023-10-04 | GSE179478 | GEO

Transcription profiling of human lymphatic endothelial cells, mouse dermal cells and human skin cells reveals an inflammation-induced mechanism for leukocyte transmigration of lymphatic vessel endothelium.

Project description:The exit of antigen-presenting cells (APC) and lymphocytes from inflamed skin to afferent lymph is vital for the initiation and maintenance of dermal immune responses. How such exit is achieved and how cells transmigrate the distinct endothelium of lymphatic vessels is however unknown. Here we show that inflammatory cytokines trigger activation of dermal lymphatic endothelial cells (LEC) leading to expression of the key leukocyte adhesion receptors ICAM-1, VCAM-1 and E-selectin, as well as a discrete panel of chemokines and other potential regulators of leukocyte transmigration. Furthermore, we show that both ICAM-1 and VCAM-1 are induced in the dermal lymphatic vessels of mice exposed to skin contact hypersensitivity where they mediate lymph node trafficking of DC via afferent lymphatics. Lastly, we show that TNF_-stimulates both DC adhesion and transmigration of dermal LEC monolayers in vitro and that the process is efficiently inhibited by ICAM-1 and VCAM-1 adhesion-blocking mAbs. These results reveal a CAM-mediated mechanism for recruiting leukocytes to the lymph nodes in inflammation and highlight the process of lymphatic transmigration as a potential new target for anti-inflammatory therapy. Experiment Overall Design: Global gene expression profile of normal dermal lymphatic endothelial cells cultured in media alone (no TNF) compared to that of normal dermal lymphatic endothelial cells stimulated with TNFalpha, 1 ng/ml for 48h.Triplicate biological samples were analyzed from human lymphatic endothelial cells (3 x controls; 3 x TNF treated) and a single sample analyzed from mouse lymphatic endothelial cells (1 x controls; 1 x TNF treated).

2008-11-07 | E-GEOD-6257 | biostudies-arrayexpress

Global gene expression profiling and antibiotic susceptibility after repeated exposure to the carbon monoxide-releasing molecule-2 (CORM-2) in multidrug-resistant ESBL-producing uropathogenic Escherichia coli

Project description:Treatment of urinary tract infections is today a challenge due to the increasing prevalence of multidrug-resistant ESBL-producing uropathogenic Escherichia coli (UPEC). There is an urgent need for new treatment strategies for multidrug-resistant UPEC and preferably with targets that have low potential for development of resistance. Carbon monoxide-releasing molecules (CORMs) are novel and potent antibacterial agents. The present study examines the transcriptomic targets of CORM-2 in a multidrug-resistant ESBL-producing UPEC isolate (ESBL7) in response to a single exposure to CORM-2 and after repeated exposure to CORM-2. The bacterial viability and minimal inhibitory concentration (MIC) were also examined after repeated exposure to CORM-2. Microarray analysis revealed that a wide range of processes were affected by CORM-2, including a general trend of down-regulation in energy metabolism and biosynthesis pathways and up-regulation of the SOS response and DNA repair. Several genes involved in virulence (ibpB), antibiotic resistance (marAB, mdtABC) and biofilm formation (bhsA, yfgF) were up-regulated, while some genes involved in virulence (kpsC, fepCEG, entABE), antibiotic resistance (evgA) and biofilm formation (artIP) were down-regulated. Repeated exposure to CORM-2 did not alter the gene expression patterns, the growth inhibitory response to CORM-2 or the MIC values for CORM-2, cefotaxime, ciprofloxacin and trimethoprim.

2016-10-06 | GSE87627 | GEO

Effect of Ginsenoside Rb1 on inflammatory reaction and odontogenic differentiation of human dental pulp cell

Project description:Ginsenoside Rb1 (G-Rb1) has been reported to diminish inflammation associated with diseases. We investigated the effect of G-Rb1 on the inflammatory reactions and the odontogenic differentiation of human dental pulp cells (hDPCs). G-Rb1 affected the levels of TNF-α, IL-6, and IL-8, as these showed reduced levels with exposure to lipopolysaccharide (LPS). Additionally, less mRNA and protein expressions of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were shown. G-Rb1 suppressed the LPS-induced increase of cell adhesion molecules and inflammatory cytokines, while also inhibiting PI3K/Akt, phosphorylation of NF-κB transcription factors, ERK and JNK of MAPK signaling in hDPCs.

2024-02-18 | GSE255672 | GEO

HUVEC gene profile after TNF-stimulation

Project description:HUVEC were left untreated or stimulated for 5h with 2 ng/ml TNF. Comparsion of the gene profiles revealed TNF-mediated gene expression changes in HUVEC. Keywords: parallel sample

2005-05-12 | GSE2639 | GEO

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