Kang Y, Kim W, Hu B, et al. Involvement of TL1A and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis

Department of Genetic Engineering, Kyungpook National University, Taegu 702-701, Republic of Korea.
Cytokine (Impact Factor: 2.66). 04/2005; 29(5):229-35. DOI: 10.1016/j.cyto.2004.12.001
Source: PubMed


TL1A (VEGI/TNFSF15) is the ligand for DR3 (TNFRSF12) and is a newly identified member of the tumor necrosis factor superfamily (TNFSF). Previously, DR3 has been shown to have a role in atherogenesis through stimulation of matrix degrading enzymes including matrix metalloproteinase (MMP)-9. Immunohistochemical staining of human carotid atherosclerotic plaques revealed a high-level expression of TL1A in regions rich in macrophage/foam cells. To investigate the role of TL1A and DR3 in the functioning of macrophage/foam cells in relation to atherogenesis, we have analyzed cellular events mediated by TL1A and DR3 in a human macrophage-like cell line, THP-1. Treatment of THP-1 cells with immobilized anti-DR3 monoclonal antibody in combination with IFN-gamma caused induction of pro-atherogenic cytokines/chemokines such as TNF-alpha, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-8. Treatment of THP-1 cells with recombinant TL1A in combination with IFN-gamma also caused induction of MMP-9 and IL-8. Furthermore, the expression of DR3 in peripheral blood monocytes was induced after atherogenic stimulation. These data suggest that TL1A and DR3 is involved in atherosclerosis via the induction of pro-inflammatory cytokines/chemokines and decreasing plaque stability by inducing extracellular matrix degrading enzymes.

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Available from: Byoung S Kwon, Jan 28, 2014
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    • "TL1A is induced in human synovial fibroblasts stimulated with TNF-α and IL-1β [4] and in monocytes stimulated with insoluble immune complexes derived from RA patients [6]. TL1A induces T cells to secrete TNF-α and IL-17 under TCR stimulation or Th17 polarization conditions, respectively [4], and it synergizes with IFN-γ and augments the production of CXCL8 and matrix metalloproteinase 9 in the human monocytic cell line THP-1 [62]. These inflammatory cytokines and chemokines are associated with RA pathology, and therefore it is possible that TL1A and these inflammatory cytokines form a vicious loop that aggravates RA pathogenesis. "
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    ABSTRACT: TNF-like ligand 1A (TL1A), which binds its cognate receptor DR3 and the decoy receptor DcR3, is an identified member of the TNF superfamily. TL1A exerts pleiotropic effects on cell proliferation, activation, and differentiation of immune cells, including helper T cells and regulatory T cells. TL1A and its two receptors expression is increased in both serum and inflamed tissues in autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Polymorphisms of the TNFSF15 gene that encodes TL1A are associated with the pathogenesis of irritable bowel syndrome, leprosy, and autoimmune diseases, including IBD, AS, and primary biliary cirrhosis (PBC). In mice, blocking of TL1A-DR3 interaction by either antagonistic antibodies or deletion of the DR3 gene attenuates the severity of multiple autoimmune diseases, whereas sustained TL1A expression on T cells or dendritic cells induces IL-13-dependent small intestinal inflammation. This suggests that modulation of TL1A-DR3 interaction may be a potential therapeutic target in several autoimmune diseases, including IBD, RA, AS, and PBC.
    Full-text · Article · Dec 2013 · Mediators of Inflammation
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    • "Interestingly, treatment of bovine aortic endothelial cells with Tnfsf15 prior to growth stimulation inhibited phospho-Rb hyperphosphorylation and induction of c-Myc [54], suggesting a regulatory loop between c-Myc and Tnfsf15 in the control of endothelial cell growth and senescence response. In addition to its role in the control of endothelial growth, Tnfsf15 has been shown to participate in inflammatory diseases [55]–[59] by directly controlling inflammatory response [60]–[63]. We found that c-Myc induced changes in Cxcl12 expression occurred mainly at RNA level. "
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    ABSTRACT: The proto-oncogene c-Myc is vital for vascular development and promotes tumor angiogenesis, but the mechanisms by which it controls blood vessel growth remain unclear. In the present work we investigated the effects of c-Myc knockdown in endothelial cell functions essential for angiogenesis to define its role in the vasculature. We provide the first evidence that reduction in c-Myc expression in endothelial cells leads to a pro-inflammatory senescent phenotype, features typically observed during vascular aging and pathologies associated with endothelial dysfunction. c-Myc knockdown in human umbilical vein endothelial cells using lentivirus expressing specific anti-c-Myc shRNA reduced proliferation and tube formation. These functional defects were associated with morphological changes, increase in senescence-associated-β-galactosidase activity, upregulation of cell cycle inhibitors and accumulation of c-Myc-deficient cells in G1-phase, indicating that c-Myc knockdown in endothelial cells induces senescence. Gene expression analysis of c-Myc-deficient endothelial cells showed that senescent phenotype was accompanied by significant upregulation of growth factors, adhesion molecules, extracellular-matrix components and remodeling proteins, and a cluster of pro-inflammatory mediators, which include Angptl4, Cxcl12, Mdk, Tgfb2 and Tnfsf15. At the peak of expression of these cytokines, transcription factors known to be involved in growth control (E2f1, Id1 and Myb) were downregulated, while those involved in inflammatory responses (RelB, Stat1, Stat2 and Stat4) were upregulated. Our results demonstrate a novel role for c-Myc in the prevention of vascular pro-inflammatory phenotype, supporting an important physiological function as a central regulator of inflammation and endothelial dysfunction.
    Preview · Article · Sep 2013 · PLoS ONE
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    • "However, the known functions of TL1A indicate that it is likely to be involved in the pathogenesis of PBS/IC. Firstly, TL1A is active in inflammation and apoptosis (17–19). The activation of NF-κB in the bladder biopsies of PBS/IC patients (predominantly in the cells of the urothelium and submucosal layer) and apoptosis of endothelial cells in this condition have been reported (20–23). "
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    ABSTRACT: Members of the tumor necrosis factor (TNF) superfamily have been revealed to be associated with painful bladder syndrome/interstitial cystitis (PBS/IC). TNF ligand-related molecule 1A (TL1A) and its receptor, death receptor 3 (DR3), belong to the TNF superfamily and have been implicated in chronic inflammatory diseases. Bladder biopsies from 8 female patients clinically diagnosed with PBS/IC according to the National Institute for Diabetes and Digestive and Kidney Diseases criteria and 8 female bladder carcinoma control patients were investigated to test the protein and mRNA expression levels of TL1A and DR3 using western blotting and real-time RT-PCR. The protein level ratio of TL1A to β-actin (IC, 0.65±0.03 vs. controls, 0.25±0.02, P<0.001) and of its receptor DR3 to β-actin (IC, 0.66±0.06 vs. controls, 0.27±0.02, P<0.001) were observed to be significantly higher in the patients with IC. The real-time RT-PCR ΔCts of TL1A minus GAPDH (IC, 7.60±0.52 vs. controls, 10.08±0.32, P<0.001) and the DR3 minus GAPDH (IC, 6.68±0.60 vs. controls, 8.99±0.61, P=0.017) were observed to be significantly lower in the patients with IC, suggesting that the mRNA levels of TL1A and DR3 were higher in the PBS/IC patients. The protein and mRNA expression of TL1A and DR3 are upregulated in the bladder tissues of PBS/IC patients and may be involved in inflammation and apoptosis in PBS/IC.
    Full-text · Article · Jan 2013 · Experimental and therapeutic medicine
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