TNF induces distinct gene expression programs in microvascular and macrovascular human endothelial cells

Viemann, Dorothee; Goebeler, Matthias; Schmid, Sybille; Nordhues, Ursula; Klimmek, Kerstin; Sorg, Clemens; Roth, Johannes

doi:10.1189/jlb.0905530

Cited by 101 publications

(86 citation statements)

References 28 publications

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“…ECs of both macrovascular (HUVECs) and microvascular origin (HMEC-1 and human dermal microvascular endothelial cells; data not shown) respond to Ni 2ϩ with activation of NF-B-and HIF-1␣-dependent signaling pathways; while there may be differences in individual gene expression patterns between both EC types (38), the basic molecular mechanisms of response to Ni 2ϩ appear still comparable. Ni 2ϩ -regulated genes can be grouped into different functional categories.…”

Section: Discussionmentioning

confidence: 99%

The Contact Allergen Nickel Triggers a Unique Inflammatory and Proangiogenic Gene Expression Pattern via Activation of NF-κB and Hypoxia-Inducible Factor-1α

Viemann

Schmidt

Tenbrock

et al. 2007

The Journal of Immunology

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Nickel compounds are prime inducers of contact allergy reactions in humans. To identify the signal transduction pathways mediating the cellular responses to nickel and to elucidate their hierarchy, we performed Affymetrix gene profiling using human primary endothelial cells, which strongly respond to nickel stimulation. Overall, we found 258 significantly modulated transcripts, comprising 140 up-regulated and 118 down-regulated genes. The bulk of those genes were identified as targets of two distinct signaling cascades, the IKK2/NF-B pathway and a proangiogenic pathway mediated by HIF-1␣, which accumulates upon exposure to nickel. Using dominant-interfering mutants and retroviral RNA interference technology, we demonstrate that both pathways act independently to regulate expression of nonoverlapping gene pools. NF-B activation mediates most of the proinflammatory responses to nickel. Nickel-dependent HIF-1␣ activation primarily modulates expression of genes involved in proliferation, survival, metabolism, and signaling, albeit the induction of some proinflammatory nickel-response genes, most prominently IL-6, which we identified as novel bona fide HIF-1␣ target in this study, is also critically dependent on this pathway. Furthermore, we provide evidence that transactivation of both transcription factors partially depends on p38 MAPK activation that contributes to the intensity of at least some target genes. Taken E ndothelial cells (ECs),3 located between blood and tissue compartments are important components of the innate immune system. Their activation by endogenous or environmental factors is a key event in the initiation of inflammatory responses. A strong activator of endothelium is the transition metal nickel that is widely distributed in a multitude of products. Contact with nickel is potentially hazardous for health: nickel compounds not only act as carcinogens in humans and animals (1) but also represent potent allergens (haptens). In industrialized countries, nickel is the most frequent cause for contact hypersensitivity reactions (2) with an estimated rate of 39% of young women being sensitized (3). Nickel is furthermore of great relevance in the context of biocompatibility of cardiovascular stents and orthopedic and dental biomedical alloys (4 -6). Nickel ions exert proinflammatory and irritant properties, which, in addition to their sensitizing capacity, provide a "second signal" in hypersensitivity reactions (7).Studying primary ECs, we earlier demonstrated that divalent nickel ions are capable of directly inducing endothelial adhesion molecules such as ICAM-1, VCAM-1, and E-selectin (8). Further analysis revealed that transcription of these genes is mediated via the IKK2/IB␣/NF-B signal transduction pathway, which is activated in response to soluble nickel compounds but not to other divalent cations (9, 10). NF-B activation is initiated by IKK2-mediated phosphorylation and subsequent proteasomal degradation of IB proteins, which allows nuclear translocation and binding of the transcription factor...

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Section: Discussionmentioning

confidence: 99%

The Contact Allergen Nickel Triggers a Unique Inflammatory and Proangiogenic Gene Expression Pattern via Activation of NF-κB and Hypoxia-Inducible Factor-1α

Viemann

Schmidt

Tenbrock

et al. 2007

The Journal of Immunology

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“…Gene sets used in this analysis were described previously [GSE3151, GSE3158 ] or were generated from existing datasets. Additional datasets for pathway signatures were: STAT3 (Dauer et al, 2005), TNF [GSE2638 and GSE2639 (Viemann et al, 2006)], RHOA [GSE5913 (Berenjeno et al, 2007)], TGFβ [GSE1724 (Renzoni et al, 2004)], endotoxin [GSE3284 (Calvano et al, 2005)] and immune (Galon et al, 2006). The signatures were applied to several datasets including the developmental dataset [http://breast-cancer-research.com/content/ supplementary/bcr753-s1.txt ] and the pubertal dataset [GSE6453 (McBryan et al, 2007)].…”

Section: Pathway Signaturesmentioning

confidence: 99%

Patterns of cell signaling pathway activation that characterize mammary development

et al. 2008

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Previous work has detailed the histological and biochemical changes associated with mammary development and remodeling. We have now made use of gene expression profiling, and in particular of the previously described signatures of cell signaling pathway activation, to explore the events associated with mammary gland development. We find that there is elevated E2F-specific pathway activity prior to lactation and relatively low levels of other important signaling pathways, such as RAS, MYC and SRC. Upon lactation and continuing into the involution phase, these patterns reverse with a dramatic increase in RAS, SRC and MYC pathway activity and a decline in E2F activity. At the end of involution, these patterns return to that of the adult non-lactating mammary gland. The importance of the changes in E2F pathway activity, particularly during the proliferative phase of mammary development, was confirmed through the analysis of mice deficient for various E2F proteins. Taken together, these results reveal a complex pattern of pathway activity in relation to the various phases of mammary gland development.

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“…The gene expression alternations induced after these treatments were studied using pig oligonucleotide 13K microarray and quantitative real-time PCR. In an effort to find molecules unique to the porcine endothelial cell activation process and the underlying mechanism, we compared our results with results from previous studies with human endothelial cells [31,32,36,37]. We found that some mRNA species are uniquely overexpressed in the activated porcine endothelial cells but not in human cells.…”

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confidence: 55%

Porcine Aortic Endothelial Cell Genes Responsive to Selected Inflammatory Stimulators

Yeom

Shin

Kim

et al. 2009

The Journal of Veterinary Medical Science

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ABSTRACT. Use of porcine tissues has been suggested as a promising solution for severe shortage of transplantable human organs. The immediate hurdle for xenotransplantation is acute immune/inflammatory vascular rejection of the transplant. Because endothelial cells play a key role in the initiation and the amplification of inflammation, alteration of gene expression in human endothelial cells, by various inflammatory stimulators has been studied extensively. However, transcriptional changes induced by human and other inflammatory stimulators in porcine endothelial cells have thus far not been studied. In this study, we treated porcine endothelial cells with human tumor necrosis factor (TNF)-, porcine interferon (IFN)-, H 2 O 2 and lypopolysaccharide (LPS) and profiled transcriptional change at 1 hr, 6 hr and 24 hr, using pig oligonucleotide 13K microarray. We found that mRNA species such as chemokine (C-X-C motif) ligand 6 (CXCL6) and Cathepsin S were significantly induced in porcine endothelial cells, as was previously reported with human endothelial cell. We also found that mRNA species including secreted frizzled-related protein 2 (SFRP2), radical S-adenosyl methionine domain containing 2 (RSAD2), structure specific recognition protein 1 (SSRP1) also were highly overexpressed in porcine endothelial cells. This result shows clues to understand underlying mechanisms of xenotransplantation rejection and the highly responsive porcine genes may serve as novel targets to be regulated for improving the function of grafted porcine donor organs.

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TNF induces distinct gene expression programs in microvascular and macrovascular human endothelial cells

Cited by 101 publications

References 28 publications

The Contact Allergen Nickel Triggers a Unique Inflammatory and Proangiogenic Gene Expression Pattern via Activation of NF-κB and Hypoxia-Inducible Factor-1α

The Contact Allergen Nickel Triggers a Unique Inflammatory and Proangiogenic Gene Expression Pattern via Activation of NF-κB and Hypoxia-Inducible Factor-1α

Patterns of cell signaling pathway activation that characterize mammary development

Porcine Aortic Endothelial Cell Genes Responsive to Selected Inflammatory Stimulators

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