Chronic Inflammation and Protection from Acute Hepatitis in Transgenic Mice Expressing TNF in Endothelial Cells

Willuweit, Antje; Sass, Gabriele; Schöneberg, Annette; Eisel, Ulrich; Tiegs, Gisa; Clauss, Matthias

doi:10.4049/jimmunol.167.7.3944

Cited by 40 publications

(39 citation statements)

References 56 publications

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“…It has been reported that an overexpression of VCAM-1 leads to inflammation and an edema that is characterized by an immune infiltrate (63)(64)(65). The ragged animal has been characterized with an edematous phenotype, and, yet, we have demonstrated here a marked reduction in the level of VCAM-1 expression.…”

Section: Vcam-1 Expression In Lung Skeletal Muscle and Skin Is Signmentioning

confidence: 44%

The VCAM-1 Gene That Encodes the Vascular Cell Adhesion Molecule Is a Target of the Sry-related High Mobility Group Box Gene, Sox18

Hosking

Wang

Downes

et al. 2004

Journal of Biological Chemistry

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VCAM-1 (vascular cell adhesion molecule-1) and Sox18 are involved in vascular development. VCAM-1 is an important adhesion molecule that is expressed on endothelial cells and has a critical role in endothelial activation, inflammation, lymphatic pathophysiology, and atherogenesis. The Sry-related high mobility group box factor Sox18 has previously been implicated in endothelial pathologies. Mutations in human and mouse Sox18 leads to hypotrichosis and lymphedema. Furthermore, both Sox18 and VCAM-1 have very similar spatio-temporal patterns of expression, which is suggestive of crosstalk. We use biochemical techniques, cell culture systems, and the ragged opossum (RaOP) mouse model with a naturally occurring mutation in Sox18 to demonstrate that VCAM-1 is an important target of Sox18. Transfection, site-specific mutagenesis, and gel shift analyses demonstrated that Sox18 directly targeted and trans-activated VCAM-1 expression. Importantly, the naturally occurring Sox18 mutant attenuates the expression and activation of VCAM-1 in vitro. Furthermore, in vivo quantitation of VCAM-1 mRNA levels in wild type and RaOP mice demonstrates that RaOP animals show a dramatic and significant reduction in VCAM-1 mRNA expression in lung, skin, and skeletal muscle. Our observation that the VCAM-1 gene is an important target of SOX18 provides the first molecular insights into the vascular abnormalities in the mouse mutant ragged and the human hypotrichosislymphedema-telangiectasia disorder.

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Section: Vcam-1 Expression In Lung Skeletal Muscle and Skin Is Signmentioning

confidence: 44%

The VCAM-1 Gene That Encodes the Vascular Cell Adhesion Molecule Is a Target of the Sry-related High Mobility Group Box Gene, Sox18

Hosking

Wang

Downes

et al. 2004

Journal of Biological Chemistry

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“…This notion is further supported by analysis of the Tie2-tmTNFα mice. In these mice, endothelial cells exhibit a chronic activated phenotype as result of endothelial-specific constitutive expression of the TNFα membranebound form [29,30] and not in response to exogenous TNFα. As a result of endothelial cell activation, we found that J2 expression was upregulated in BM endothelial cells and that it correlated with increased Notch activation on Lin − Sca + Kit + hematopoietic progenitors.…”

Section: Discussionmentioning

confidence: 99%

“…To further corroborate the results obtained with soluble TNFα, we analyzed the levels of J2 expression and Notch signaling activation in a model of endothelial cell activation by using Tie2-tmTNFα transgenic mice. In Tie2-tmTNFα transgenic mouse, a transmembrane, noncleavable form [mTNFD1-9,K(11)E] of TNFα is expressed under the control of the Tie2 promoter, in conjunction with an intronic enhancer element used to drive endothelial-specific expression [30]. In these mice, endothelial cells exhibit a chronic activated phenotype as result of constitutive expression of the TNFα membrane-bound form [29,30].…”

Section: Upregulation Of Notch Signaling In the Bone Marrow Microenvimentioning

confidence: 99%

“…In Tie2-tmTNFα transgenic mouse, a transmembrane, noncleavable form [mTNFD1-9,K(11)E] of TNFα is expressed under the control of the Tie2 promoter, in conjunction with an intronic enhancer element used to drive endothelial-specific expression [30]. In these mice, endothelial cells exhibit a chronic activated phenotype as result of constitutive expression of the TNFα membrane-bound form [29,30]. Analysis of J2 expression in Tie2-tmTNFα mice showed increased levels of J2 on BM cells with endothelial immunophenotype CD45 − CD31 + FLK1 + , compared to nontransgenic (WT) controls (Fig.…”

Section: Upregulation Of Notch Signaling In the Bone Marrow Microenvimentioning

confidence: 99%

“…Hes5-GFP mice were BAC transgenics from the NIDS GENSAT project (Rockefeller University, www.gensat.org). Tie2-tmTNFα transgenic mice and WT non transgenic littermates were described in [29,30]. Mice were matched for gender and analyzed at 4-5 weeks of age.…”

Section: Micementioning

confidence: 99%

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Tumor necrosis factor-α and endothelial cells modulate Notch signaling in the bone marrow microenvironment during inflammation

Fernández

Rodríguez

Huang

et al. 2008

Experimental Hematology

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Objective-Homeostasis of the hematopoietic compartment is challenged and maintained during conditions of stress by mechanisms that are poorly defined. To understand how the bone marrow (BM) microenvironment influences hematopoiesis, we explored the role of Notch signaling and bone marrow endothelial cells in providing microenvironmental cues to hematopoietic cells in the presence of inflammatory stimuli.Methods-The human BM endothelial cell line BMEC and primary human BM endothelial cells were analyzed for expression of Notch ligands and the ability to expand hematopoietic progenitors in an in vitro co-culture system. In vivo experiments were carried out to identify modulation of Notch signaling in BM endothelial and hematopoietic cells in mice challenged with TNFα or LPS, or in Tie2-tmTNFα transgenic mice characterized by constitutive TNFα activation.Results-BM endothelial cells were found to express Jagged ligands and to greatly support progenitor's colony-forming ability. This effect was markedly decreased by Notch antagonists and augmented by increasing levels of Jagged2. Physiologic upregulation of Jagged2 expression on BMEC was observed upon TNFα activation. Injection of TNFα or LPS upregulated 3 to 4 fold Jagged2 expression on murine BM endothelial cells in vivo and resulted in increased Notch

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Soluble human p55 and p75 tumor necrosis factor receptors reverse spontaneous arthritis in transgenic mice expressing transmembrane tumor necrosis factor α

Edwards¹,

Bendele²,

Reznikov³

et al. 2006

Arthritis & Rheumatism

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Objective. The roles of the transmembrane and secreted forms of tumor necrosis factor ␣ (TNF␣) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNF␣ have shown varying efficacy in RA patients, suggesting that anti-TNF␣ agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNF␣) and secreted TNF␣. In this study, TNF␣-knockout (TNF␣-KO) mice that were genetically altered to express elevated levels of tmTNF␣ were constructed to further understand the roles of the 17-kd secreted, trimeric, and 26-kd transmembrane forms of TNF␣.Methods. A speed-congenic mating scheme was used to generate 3 unique strains of mice: 1) transgenic tmTgA86 mice overexpressing 26-kd tmTNF␣ and also secreting 17-kd trimeric TNF␣ (tmTNF␣-transgenic), 2) TNF␣ ؊/؊ mice (TNF␣-KO), and 3) transgenic mice overexpressing tmTNF␣ backcrossed to TNF␣-KO mice (tmTNF␣-transgenic/TNF␣-KO). Mice were treated with phosphate buffered saline (as vehicle control), dexamethasone (as positive control), or modified recombinant human soluble TNF receptor (sTNFR) p55 or p75, and were assessed clinically and histopathologically for signs of inflammation and development of arthritis.Results. The tmTNF␣-transgenic/TNF␣-KO mice were born with crinkled tails and spinal deformities similar to those in ankylosing spondylitis. By 2-4 weeks, these mice developed symmetric inflammatory arthritis, characterized by tissue swelling, pannus formation, and bone deformities. The tmTNF␣-transgenic mice also developed spontaneous-onset arthritis, but at a slower rate (100% incidence by 10-12 weeks). Clinical and histologic progression of arthritis in the tmTNF␣-transgenic/TNF␣-KO mice was reduced by treatment with dexamethasone or with the p55 or p75 sTNFR (69% and 63% reduction in total histologic score, respectively).Conclusion. These data show that arthritis is sufficiently initiated and maintained in tmTNF␣-transgenic/TNF␣-KO mice, and that it can be neutralized by recombinant human p55 or p75 sTNFR, resulting in amelioration of the biologic and subsequent histologic destructive effects of tmTNF␣.Numerous investigations have pointed to a key role of the proinflammatory pleiotropic cytokines tumor necrosis factor ␣ (TNF␣) and interleukin-1 (IL-1) in Dr.

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Chronic Inflammation and Protection from Acute Hepatitis in Transgenic Mice Expressing TNF in Endothelial Cells

Cited by 40 publications

References 56 publications

The VCAM-1 Gene That Encodes the Vascular Cell Adhesion Molecule Is a Target of the Sry-related High Mobility Group Box Gene, Sox18

The VCAM-1 Gene That Encodes the Vascular Cell Adhesion Molecule Is a Target of the Sry-related High Mobility Group Box Gene, Sox18

Tumor necrosis factor-α and endothelial cells modulate Notch signaling in the bone marrow microenvironment during inflammation

Soluble human p55 and p75 tumor necrosis factor receptors reverse spontaneous arthritis in transgenic mice expressing transmembrane tumor necrosis factor α

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