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LIGHT is involved in the pathogenesis of rheumatoid arthritis by inducing the expression of pro-inflammatory cytokines and MMP-9 in macrophages

Department of Genetic Engineering, Kyungpook National University, Taegu 702-701, Korea.
Immunology (Impact Factor: 3.74). 03/2005; 114(2):272-9. DOI: 10.1111/j.1365-2567.2004.02004.x
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ABSTRACT Macrophages play a crucial role in the perpetuation of inflammation and irreversible cartilage damage during the development of rheumatoid arthritis (RA). LIGHT (TNFSF14) and its receptor TR2 (TNFRSF14) are known to have pro-inflammatory activities in foam cells of atherosclerotic plaques. We tested a hypothesis that LIGHT and TR2 are involved in activation of monocyte/macrophages in RA synovium. Immunohistochemical analysis of RA synovial tissue samples revealed that both LIGHT and TR2 are expressed in CD68 positive macrophages. In contrast, synovial tissue samples from osteoarthritis (OA) patients failed to reveal the expression of LIGHT. Expression of TR2 in RA synovial macrophages was also detected using flow cytometry analysis. To identify the role of LIGHT in the functioning of macrophages in RA, we isolated macrophage enriched cells from RA synovial fluid and stimulated them with LIGHT. LIGHT induced expression of matrix metalloproteinase-9 and pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8. These data indicate that LIGHT and TR2 expressed in macrophages are involved in the pathogenesis of RA by inducing the expression pro-inflammatory cytokines and matrix degrading enzymes.

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Available from: Yoon Joong Kang, Feb 28, 2014
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    • "Studies also suggest that TNFSF14 can induce an inflammatory response in endothelial cells via upregulation of ICAM1, VCAM1 and IL8 production and expression (Otterdal et al, 2006), and in monocytes through upregulation of CCL2 (MCP-1) and IL8 (Otterdal et al, 2006). TNFSF14 is thought to contribute to inflammation in rheumatoid arthritis (Kim et al, 2005), hepatitis (Anand et al, 2006) and atherogenesis (Lee et al, 2001), and has been suggested as a potential therapeutic target in atherosclerosis (Sandberg et al, 2009), where it plays a pro-thrombotic and pro-inflammatory role (Aukrust et al, 2011). "
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    ABSTRACT: Chronic vascular inflammation and endothelial activation may initiate vaso-occlusion in sickle cell disease (SCD). TNFSF14 (CD258; LIGHT), a recently-identified pro-thrombotic and pro-inflammatory tumour necrosis factor (TNF)-superfamily cytokine, has a potent activating effect on endothelial cells. We evaluated whether TNFSF14 production is altered in SCD and whether platelets contribute to this production. TNFSF14 was measured in platelet-free plasma from healthy-control individuals (CON), steady-state sickle cell anaemia (SCA), SCA on hydroxycarbamide therapy (SCAHC) and haemoglobin SC (HbSC) patients. Mean plasma TNFSF14 was significantly increased in SCA, SCAHC and HbSC, compared to CON individuals. In SCA/SCAHC patients, plasma TNFSF14, showed no correlation with haematological variables, but was significantly correlated with serum lactate dehydrogenase and inflammatory markers (CD40LG , IL8 and ICAM1). Platelet-membrane TNFSF14 expression was significantly augmented on SCA platelets, and correlated with platelet activation; furthermore, measurement of platelet TNFSF14 release indicated that platelets may be a major source of circulating TNFSF14 in SCA. Interestingly, high plasma TNFSF14 was significantly associated with elevated tricuspid regurgitant velocity (≥2·5 m/s) in a population of SCA/SCAHC patients. The pro-inflammatory and atherogenic cytokine, TNFSF14, could contribute to endothelial activation and inflammation in SCA; future investigations may confirm whether this protein contributes to major clinical complications of the disease, such as pulmonary hypertension, and represents a potential therapeutic target.
    British Journal of Haematology 07/2012; 158(6):788-97. DOI:10.1111/j.1365-2141.2012.09218.x · 4.96 Impact Factor
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    • "Thus, LIGHT treatment augmented CXCL9, CXCL10, and CXCL11 production in IFN-g-stimulated human dermal fibroblasts at both mRNA and protein levels. LIGHT enhances CXCL9, CXCL10, and CXCL11 expression by IFN-c-treated dermal fibroblasts via phosphorylation of IjBa We next examined whether LIGHT would induce phosphorylation of inhibitor kBa (IkBa) in dermal fibroblasts, as was previously reported in other cell types (Marsters et al., 1997; Kim et al., 2005; Hosokawa et al., 2010). Phosphorylation of IkBa triggers activation and enhanced transcriptional activity of NF-kB. "
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    ABSTRACT: LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes) is a ligand for HVEM. LIGHT-HVEM interactions are important in T helper type 1 (Th1) immune responses. In some cases with early stages of cutaneous T cell lymphoma (CTCL), IL-2, IFN-γ, and Th1 chemokines are expressed in lesional skin, while IL-4, IL-5, and Th2 chemokines are dominant in advanced CTCL. In this study, we investigated roles of LIGHT and HVEM in the microenvironment of CTCL. LIGHT enhanced production of Th1 chemokines, such as CXC chemokine ligand (CXCL) 9, CXCL10, and CXCL11, from IFN-γ-treated dermal fibroblasts via phosphorylation of inhibitor κBα. Messenger RNA levels of these chemokines were increased in lesional skin of early CTCL. Interestingly, while LIGHT expression in CTCL skin correlated with disease progression, HVEM expression was significantly decreased in advanced CTCL skin. HVEM was detected in dermal fibroblasts in early CTCL skin, but not in advanced CTCL skin in situ. These results suggest that low HVEM expression on dermal fibroblasts in advanced CTCL skin attenuates expression of Th1 chemokines, which may contribute to a shift to a Th2-dominant microenvironment as disease progresses.
    Journal of Investigative Dermatology 02/2012; 132(4):1280-9. DOI:10.1038/jid.2011.470 · 6.37 Impact Factor
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    • "HVEM is widely and constitutively expressed in various human and rodent tissues, and strongly expressed on resting/activated immune cells (e.g., T cells, B cells, and monocytes) and non-immune cells (e.g., endothelial cells and adipocytes) [6] [8] [9]. The interaction between HVEM and its ligand is involved in various inflammatory processes, and thus is implicated in the development of a number of inflammatory diseases (e.g., inflammatory bowel disease, rheumatoid arthritis, and nephritis) [8] [10]. Blockade of HVEM/LIGHT activation attenuates the severity of autoimmune diseases such as type I diabetes mellitus and inflammatory bowel disease [11] [12], and therefore HVEM and its ligand are considered to be therapeutic targets in those inflammatory diseases. "
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    ABSTRACT: HVEM is a member of the TNF receptor superfamily that plays a role in the development of various inflammatory diseases. In this study, we show that HVEM deficiency attenuates adipose tissue inflammatory responses and glucose intolerance in diet-induced obesity. Feeding a high-fat diet (HFD) to HVEM-deficient mice elicited a reduction in the number of macrophages and T cells infiltrated into adipose tissue. Proinflammatory cytokine levels in the adipose tissue decreased in HFD-fed HVEM-deficient mice, while levels of the anti-inflammatory cytokine IL-10 increased. Moreover, glucose intolerance and insulin sensitivity were markedly improved in the HFD-fed HVEM-deficient mice. These findings indicate that HVEM may be a useful target for combating obesity-induced inflammatory responses and insulin resistance.
    FEBS letters 06/2011; 585(14):2285-90. DOI:10.1016/j.febslet.2011.05.057 · 3.34 Impact Factor
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