Objective-Suppressors of cytokine signaling (SOCS) proteins are intracellular regulators of receptor signal transduction, mainly Janus kinase/signal transducers and activators of transcription (JAK/STAT). We investigated the effects of SOCS modulation on the JAK/STAT-dependent responses in vascular cells, and their implication in atherosclerotic plaque development. Methods and Results-Immunohistochemistry in human plaques revealed a high expression of SOCS1 and SOCS3 by vascular smooth muscle cells (VSMCs) and macrophages in the inflammatory region of the shoulders, when compared to the fibrous area. SOCS were also increased in aortic lesions from apoE Ϫ/Ϫ mice. In cultured VSMCs, endothelial cells, and monocytes, SOCS1 and SOCS3 were transiently induced by proinflammatory cytokines, proatherogenic lipoproteins, and immune molecules. Furthermore, overexpression of SOCS suppressed STAT activation and reduced inflammatory gene expression and cell growth, whereas SOCS knockdown increased these cell responses. In vivo, antisense oligodeoxynucleotides targeting SOCS3 exacerbated the atherosclerotic process in apoE Ϫ/Ϫ mice by increasing the size, leukocyte content, and chemokine expression in the lesions. Key Words: atherosclerosis Ⅲ inflammation Ⅲ signal transduction Ⅲ proliferation Ⅲ chemokines A therosclerosis is a chronic inflammatory disease that involves a complex interaction of the artery wall and its cellular components, lipoproteins, and circulating blood elements. 1 Leukocyte invasion and vascular smooth muscle cell (VSMC) proliferation are key early events in lesion development. 2 Low-density lipoproteins (LDL) and cytokines, such as interferon ␥ (IFN␥) and interleukin-6 (IL-6), influence the dynamics of vascular cell function and are main mediators of inflammation during atherogenesis. 2,3 Native and modified forms of LDL induce a variety of biological properties, including cytokine expression, changes in monocyte/macrophages motility and arterial vasomotricity, and VSMC mitogenesis. 4,5 IFN␥ is expressed in human and experimental plaques, and induces the expression of major histocompatibility complex-II, downregulates scavenger receptors, and modulates vascular cell proliferation. 2,6 IL-6 is secreted from endothelial cells (ECs), VSMCs, and leukocytes, and has multiple biological activities, including lymphocyte activation, acute-phase proteins induction, and proliferation. 7,8 Evidence supports the involvement of cellular and humoral immune responses in atherosclerosis, from its initiation to its thrombotic complication. 9 Elevated levels of LDL-containing immune complexes (ICs) and their IgG Fc receptors (Fc␥R) have been found in atherosclerotic patients. 10 Furthermore, Fc␥R mediates the clearance of ICs containing LDL and foam cell formation, 10 and Fc␥R activation in vascular cells is critical for atherosclerosis development in mice. 11 The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is an essential intracellular mechanism of cytokines and other stimuli tha...
Nuclear factor (NF)-kappa B regulates several genes implicated in the inflammatory response and represents an interesting therapeutic target. We examined the effects of gliotoxin (a fungal metabolite) and parthenolide (a plant extract), which possess anti-inflammatory activities in vitro, on the progression of experimental glomerulonephritis. In the anti-Thy 1.1 rat model, gliotoxin (75 micro g/rat/day, 10 days, n = 18 rats) markedly reduced proteinuria, glomerular lesions, and monocyte infiltration. In anti-mesangial cell nephritis in mice, parthenolide (70 micro g/mouse/day, 7 days, n = 17 mice) significantly decreased proteinuria, hematuria, and glomerular proliferation. NF-kappa B activity, localized in glomerular and tubular cells, was attenuated by either gliotoxin or parthenolide, in association with diminished renal expression of monocyte chemoattractant protein-1 and inducible nitric oxide synthase. In cultured mesangial cells and monocytes, gliotoxin and parthenolide inhibited NF-kappa B activation and expression of inflammatory genes induced by lipopolysaccharide and cytokines, by blocking the phosphorylation/degradation of the I kappa B(alpha) subunit. In summary, gliotoxin and parthenolide prevent proteinuria and renal lesions by inhibiting NF-kappa B activation and expression of regulated genes. This may represent a novel approach for the treatment of immune and inflammatory renal diseases.
Abstract-IgG Fc receptors (Fc␥Rs) play a role in activating the immune system and in maintaining peripheral tolerance, but their role in atherosclerosis is unknown. We generated double-knockout (DKO) mice by crossing apolipoprotein E-deficient mice (apoE Ϫ/Ϫ ) with Fc␥R ␥ chain-deficient mice (␥ Ϫ/Ϫ ). The size of atherosclerotic lesions along the aorta was approximately 50% lower in DKO compared with apoE Ϫ/Ϫ control mice, without differences in serum lipid levels. The macrophage and T-cell content of lesions in the DKO were reduced by 49Ϯ6% and 56Ϯ8%, respectively, compared with the content in apoE Ϫ/Ϫ lesions. Furthermore, the expression of monocyte chemoattractant protein-1 (MCP-1), RANTES (Regulated on Activated Normal T-cell Expressed and Secreted), and intercellular adhesion molecule-1 (ICAM-1) and the activation of nuclear factor-B (NF-B) were significantly reduced in aortic lesions from DKO mice. In vitro, vascular smooth muscle cells (VSMCs) from both ␥ Ϫ/Ϫ and DKO mice failed to respond to immune complexes, as shown by impaired chemokine expression and NF-B activation. ApoE Ϫ/Ϫ mice have higher levels of activating Fc␥RI and Fc␥RIIIA, and inhibitory Fc␥RIIB, compared with wild-type mice. The DKO mice express only the inhibitory Fc␥RIIB receptor. We conclude that Fc␥R deficiency limits development and progression of atherosclerosis. In addition to leukocytes, Fc␥R activation in VSMCs contributes to the inflammatory process, in part, by regulating chemokine expression and leukocyte invasion of the vessel wall. These results underscore the critical role of Fc␥Rs in atherogenesis and support the use of immunotherapy in the treatment of this disease. Key Words: Fc receptors Ⅲ atherosclerosis Ⅲ double-knockout mice Ⅲ immune complexes A therosclerosis is a chronic inflammatory disease of the arterial wall characterized by progressive accumulation of lipids, cells, and extracellular matrix. In recent years, the immune processes associated to atherogenesis have received considerable attention. Studies in both humans and animals have demonstrated that atheromatous lesions at all stage of development contain a wide variety of cells and molecules characteristic of immune system, such as macrophages, lymphocytes, CD40, interferon-␥, major histocompatibility complex-II, complement, and antibodies (Abs). [1][2][3][4] In addition, congenital deficiency of macrophages, T and B lymphocytes, or even the inhibition of their mediators has resulted in the reduction of atherosclerotic lesion. 1,3 One of the critical steps in atherogenesis is the accumulation within the arterial intima of cholesteryl ester-laden foam cells, many of them derived from macrophages, whose formation is ultimately dependent on the uptake of various forms of low-density lipoproteins (LDLs). 1,2 Although emphasis has been placed on scavenger receptors, foam-cell development may also be influenced by lipoprotein interaction with other receptors, such as LDL receptors, very-low-density lipoprotein (VLDL) receptors, and IgG Fc (Fc␥Rs) receptors. 5 Diff...
NF-kappaB inhibition by PTN retards atherosclerotic lesions in apoE mice, by reducing lesion size and changing plaque composition. This natural compound could represent a novel therapeutic approach to inflammation during vascular damage.
BACKGROUND Successful embryo implantation is a complex process that requires the coordination of a series of events, involving both the embryo and the maternal endometrium. Key to this process is the intricate cascade of molecular mechanisms regulated by endocrine, paracrine and autocrine modulators of embryonic and maternal origin. Despite significant progress in ART, implantation failure still affects numerous infertile couples worldwide and fewer than 10% of embryos successfully implant. Improved selection of both the viable embryos and the optimal endometrial phenotype for transfer remains crucial to enhancing implantation chances. However, both classical morphological embryo selection and new strategies incorporated into clinical practice, such as embryonic genetic analysis, morphokinetics or ultrasound endometrial dating, remain insufficient to predict successful implantation. Additionally, no techniques are widely applied to analyse molecular signals involved in the embryo–uterine interaction. More reliable biological markers to predict embryo and uterine reproductive competence are needed to improve pregnancy outcomes. Recent years have seen a trend towards ‘omics’ methods, which enable the assessment of complete endometrial and embryonic molecular profiles during implantation. Omics have advanced our knowledge of the implantation process, identifying potential but rarely implemented biomarkers of successful implantation. OBJECTIVE AND RATIONALE Differences between the findings of published omics studies, and perhaps because embryonic and endometrial molecular signatures were often not investigated jointly, have prevented firm conclusions being reached. A timely review summarizing omics studies on the molecular determinants of human implantation in both the embryo and the endometrium will help facilitate integrative and reliable omics approaches to enhance ART outcomes. SEARCH METHODS In order to provide a comprehensive review of the literature published up to September 2019, Medline databases were searched using keywords pertaining to omics, including ‘transcriptome’, ‘proteome’, ‘secretome’, ‘metabolome’ and ‘expression profiles’, combined with terms related to implantation, such as ‘endometrial receptivity’, ‘embryo viability’ and ‘embryo implantation’. No language restrictions were imposed. References from articles were also used for additional literature. OUTCOMES Here we provide a complete summary of the major achievements in human implantation research supplied by omics approaches, highlighting their potential to improve reproductive outcomes while fully elucidating the implantation mechanism. The review highlights the existence of discrepancies among the postulated biomarkers from studies on embryo viability or endometrial receptivity, even using the same omic analysis. WIDER IMPLICATIONS Despite the huge amount of biomarker information provided by omics, we still do not have enough evidence to link data from all omics with an implantation outcome. However, in the foreseeable future, application of minimally or non-invasive omics tools, together with a more integrative interpretation of uniformly collected data, will help to overcome the difficulties for clinical implementation of omics tools. Omics assays of the embryo and endometrium are being proposed or already being used as diagnostic tools for personalised single-embryo transfer in the most favourable endometrial environment, avoiding the risk of multiple pregnancies and ensuring better pregnancy rates.
The mesangium occupies a central anatomical position in the glomerulus, and also plays an important regulatory role in immune-mediated glomerular diseases, with an active participation in the response to local inflammation. In general, the mesangial cell responses to the pathological stimuli are associated with the main events of glomerular injury: leukocyte infiltration, cell proliferation and fibrosis. Leukocyte migration and infiltration into the glomerulus is responsible for the initiation and amplification of glomerular injury, and is mediated by adhesion molecules and chemokines, which can be locally synthesized by mesangial cells. The increase in mesangial cell number is also due to proliferation of intrinsic mesangial cell population. Regulatory mechanisms of mesangial cell replication include a complex array of factors which control cell proliferation, survival and apoptosis. Mesangial matrix accumulation leading to glomerulosclerosis, is a consequence of an imbalance between matrix production and degradation, and is controlled by growth factors and pro-inflammatory cytokines. The initial phase of immune-mediated glomerular inflammation depends on the interaction of immune complexes with specific Fc receptors in infiltrating leukocytes and resident mesangial cells, the ability of immune complexes to activate complement system, and on local inflammatory processes. Activated mesangial cells then produce many inflammatory mediators leading to amplification of the injury. This review will focus on the biological functions of mesangial cells that contribute to glomerular injury, with special attention to immune-mediated glomerulonephritis. Furthermore, new therapies based on the pathophysiology of the mesangial cell that are being developed in experimental models are also proposed.
Suppressors of cytokine signaling (SOCS) family is
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