Atherosclerosis is a progressive disorder of the arterial wall and the underlying cause of cardiovascular diseases such as heart attack and stroke. Today, atherosclerosis is recognized as a complex disease with a strong inflammatory component. The nuclear factor-kappaB (NF-kappaB) signaling pathway regulates inflammatory responses and has been implicated in atherosclerosis. Here, we addressed the function of NF-kappaB signaling in vascular endothelial cells in the pathogenesis of atherosclerosis in vivo. Endothelium-restricted inhibition of NF-kappaB activation, achieved by ablation of NEMO/IKKgamma or expression of dominant-negative IkappaBalpha specifically in endothelial cells, resulted in strongly reduced atherosclerotic plaque formation in ApoE(-/-) mice fed with a cholesterol-rich diet. Inhibition of NF-kappaB abrogated adhesion molecule induction in endothelial cells, impaired macrophage recruitment to atherosclerotic plaques, and reduced expression of cytokines and chemokines in the aorta. Thus, endothelial NF-kappaB signaling orchestrates proinflammatory gene expression at the arterial wall and promotes the pathogenesis of atherosclerosis.
Next-generation sequencing (NGS) technology has expanded in the last decades with significant improvements in the reliability, sequencing chemistry, pipeline analyses, data interpretation and costs. Such advances make the use of NGS feasible in clinical practice today. This review describes the recent technological developments in NGS applied to the field of oncology. A number of clinical applications are reviewed, i.e., mutation detection in inherited cancer syndromes based on DNA-sequencing, detection of spliceogenic variants based on RNA-sequencing, DNA-sequencing to identify risk modifiers and application for pre-implantation genetic diagnosis, cancer somatic mutation analysis, pharmacogenetics and liquid biopsy. Conclusive remarks, clinical limitations, implications and ethical considerations that relate to the different applications are provided.
Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor–dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.
Using targeted mutagenesis in mice, we have blocked shedding of endogenous murine TNF by deleting its cleavage site. Mutant mice produce physiologically regulated levels of transmembrane TNF (tmTNF), which suffice to support thymocyte proliferation but cannot substitute for the hepatotoxic activities of wild-type TNF following LPS/Dgalactosamine challenge in vivo and are not sufficient to support secondary lymphoid organ structure and function. Notably, however, tmTNF is capable of exerting antiListerial host defenses while remaining inadequate to mediate arthritogenic functions, as tested in the tristetraprolin-deficient model of TNF-dependent arthritis. Most interestingly, in the EAE model of autoimmune demyelination, tmTNF suppresses disease onset and progression and retains the autoimmune suppressive properties of wild-type TNF. Together, these results indicate that tmTNF preserves a subset of the beneficial activities of TNF while lacking detrimental effects. These data support the hypothesis that selective targeting of soluble TNF may offer several advantages over complete blockade of TNF in the treatment of chronic inflammation and autoimmunity.Supporting information for this article is available at: http://www.wiley-vch.de/contents/jc_2040/2006/35921_s.pdf IntroductionOriginally identified as an endotoxin-induced serum factor that causes necrosis of tumors [1] and/or cachexia [2], TNF is currently known to mediate a wide array of biological activities [3, 4]. TNF is produced in response to bacterial toxins, inflammatory products and other stimuli mainly by cells of the myeloid lineage, with additional producers including B and T lymphocytes, NK cells, microglia, astrocytes and adipocytes [3]. TNF is bioactive both as a transmembrane protein and as a homotrimeric secreted molecule [5] and mediates its effects through two distinct TNF receptors, p55TNFR (TNFRI) and p75TNFR (TNFRII) [6]. Transmembrane TNF (tmTNF) appears superior to soluble TNF in activating the p75TNFR, while at physiological concentrations soluble TNF primarily activates the p55TNFR [7]. The two types of TNF receptors share structural homology in the extracellular TNF-binding domains, but they induce separate cytoplasmic signaling pathways following receptor-ligand interaction [8]. Apoptosis and activation of NF-jB are initiated by p55TNFR, whereas p75TNFR appears to play a direct role in only a limited number of TNF responses [6,9]. Several functionally diverse proteins, such as growth factors and cytokines and including TNF, are initially synthesized as biologically active membrane-anchored molecules that are subsequently released from the cell by proteolysis [10]. Thus, surface localization may serve to restrict activity to specific microenvironments, whereas release may lead to distal effects. TNF is synthesized as a 26 kDa type II transmembrane molecule, which can be processed by a TNF-alpha converting enzyme (TACE or ADAM17), to generate secreted 17 kDa monomers that form biologically active homotrimers [11,12]. Indications for a r...
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