Necrosis Factor Family Member LIGHT Research Articles

Tumor necrosis factor family member LIGHT acts with IL-1β and TGF-β to promote airway remodeling during rhinovirus infection.

Rhinovirus (RV) can exacerbate allergen-driven asthma. However, it has been suggested that serial infections with RV may also lead to asthma-like features in childhood without prior allergen exposure. We sought to test the effects of RV infection in the absence of allergen challenge on lung tissue remodeling and to understand whether RV induced factors in common with allergen that promote remodeling. We infected C57BL/6 mice multiple times with RV in the absence or presence of allergen to assess airway remodeling. We used knockout mice and blocking reagents to determine the participation of LIGHT (TNFSF14), as well as IL-1β and TGF-β, each previously shown to contribute to lung remodeling driven by allergen. Recurrent RV infection without allergen challenge induced an increase in peribronchial smooth muscle mass and subepithelial fibrosis. Rhinovirus (RV) induced LIGHT expression in mouse lungs after infection, and alveolar epithelial cells and neutrophils were found to be potential sources of LIGHT. Accordingly, LIGHT-deficient mice, or mice where LIGHT was neutralized, displayed reduced smooth muscle mass and lung fibrosis. Recurrent RV infection also exacerbated the airway remodeling response to house dust mite allergen, and this was significantly reduced in LIGHT-deficient mice. Furthermore, neutralizing IL-1β or TGF-β also limited subepithelial fibrosis and/or smooth muscle thickness induced by RV. Rhinovirus can promote airway remodeling in the absence of allergen through upregulating common factors that also contribute to allergen-associated airway remodeling.

Role of the tumor necrosis factor family member LIGHT in the pathogenesis of atopic dermatitis.

LIGHT (the name of which is derived from "homologous to lymphotoxins, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for herpes simplex virus entry mediator, and expressed by T lymphocytes"), is a member of the tumor necrosis factor superfamily that is involved in various inflammatory diseases. To assess serum LIGHT levels in patients with atopic dermatitis (AD) before and after treatment and compare it with controls. To correlate serum LIGHT with the severity scoring of AD (SCORAD) index. Another objective is to compare LIGHT levels between lesional skin in patients with AD and controls. Twenty patients with AD and 20 healthy controls were enrolled in the study. Serum LIGHT levels were examined using an enzyme immunoassay technique. Serum total IgE levels, absolute eosinophil count, and eosinophil percentage were also done for both patients and controls. The SCORAD index was done for every patient before and after treatment. Skin LIGHT levels were analyzed using enzyme-linked immunosorbent assay kit and compared with control skin. Serum LIGHT levels in patients with AD were significantly higher than that of healthy controls and correlated positively with SCORAD index. LIGHT concentrations decreased as the symptoms were improved by treatment. A significant correlation was found on comparing the LIGHT serum levels and other established markers of disease severity. LIGHT levels in lesional skin in these patients were markedly higher than LIGHT levels in normal skin. LIGHT may play an important role in the pathogenesis of AD. This may presumably have possible future implications on the treatment of this chronic disease.

Aberrant expression of regulatory cytokine IL-35 and pattern recognition receptor NOD2 in patients with allergic asthma.

We investigated the plasma concentration of the novel regulatory cytokine IL-35 and intracytosolic pattern recognition receptors nucleotide-binding oligomerization domain (NOD)-like receptors in granulocytes and explored their potential implication in disease severity monitoring of allergic asthma. The expression of circulating IL-35 and other pro-inflammatory mediators in asthmatic patients or control subjects were evaluated using enzyme-linked immunosorbent assay (ELISA). The intracellular expressions of NOD1 and NOD2 in CCR3+ granulocytes were assessed using flow cytometry. Plasma concentrations of IL-35, IL-17A, basophil activation marker basogranulin, and eosinophilic airway inflammation biomarker periostin were significantly elevated in allergic asthmatic patients compared to non-atopic control subjects (all probability (p) <0.05). Both granulocyte markers exhibited significant and positive correlation with plasma IL-35 concentration in asthmatic patients (all p < 0.05). Significant positive correlation was also identified between plasma concentrations of IL-35 and periostin with disease severity score in asthmatic patients (both p < 0.05). The basophil activation allergenicity test was positive in allergic asthmatic patients but not in control subjects. Despite significantly elevated eosinophil count in allergic asthmatic patients, downregulation of NOD2 in CCR3+ granulocytes was observed in these patients (both p < 0.05). A negative correlation between plasma concentrations of tumor necrosis factor family member LIGHT and soluble herpesvirus entry mediator was observed in patients with elevated plasma concentration of IL-35 (p < 0.05). Aberrant expression of NOD2 in granulocytes may be contributed to the impaired innate immunity predisposing allergic asthma. IL-35 may serve as a potential surrogate biomarker for disease severity of allergic asthma.

Effect of tumor necrosis factor family member LIGHT (TNFSF14) on the activation of basophils and eosinophils interacting with bronchial epithelial cells.

Allergic asthma can cause airway structural remodeling, involving the accumulation of extracellular matrix and thickening of smooth muscle. Tumor necrosis factor (TNF) family ligand LIGHT (TNFSF14) is a cytokine that binds herpesvirus entry mediator (HVEM)/TNFRSF14 and lymphotoxin β receptor (LTβR). LIGHT induces asthmatic cytokine IL-13 and fibrogenic cytokine transforming growth factor-β release from allergic asthma-related eosinophils expressing HVEM and alveolar macrophages expressing LTβR, respectively, thereby playing crucial roles in asthmatic airway remodeling. In this study, we investigated the effects of LIGHT on the coculture of human basophils/eosinophils and bronchial epithelial BEAS-2B cells. The expression of adhesion molecules, cytokines/chemokines, and matrix metalloproteinases (MMP) was measured by flow cytometry, multiplex, assay or ELISA. Results showed that LIGHT could significantly promote intercellular adhesion, cell surface expression of intercellular adhesion molecule-1, release of airway remodeling-related IL-6, CXCL8, and MMP-9 from BEAS-2B cells upon interaction with basophils/eosinophils, probably via the intercellular interaction, cell surface receptors HVEM and LTβR on BEAS-2B cells, and extracellular signal-regulated kinase, p38 mitogen activated protein kinase, and NF-κB signaling pathways. The above results, therefore, enhance our understanding of the immunopathological roles of LIGHT in allergic asthma and shed light on the potential therapeutic targets for airway remodeling.

The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling

The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling

Inhibiting or blocking LIGHT, a TNF superfamily member, for treating airway remodeling

Evaluation of: Doherty TA, Soroosh P, Khorram N et al. The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling. Nat. Med. 17, 596–603 (2011).Individuals with chronic asthma demonstrate a progressive decline in lung function that is thought to be due to structural remodeling of the airways, characterized by subepithelial fibrosis and smooth muscle hyperplasia. Here we report on a recent publication showing that the tumor necrosis factor family member LIGHT is expressed on lung inflammatory cells after allergen exposure. Pharmacological inhibition of LIGHT using a fusion protein between the IgG Fc domain and lymphotoxin-β-receptor reduces lung fibrosis, smooth muscle hyperplasia and airway hyperresponsiveness in mouse models of chronic asthma, despite having little effect on airway eosinophilia. LIGHT-deficient mice also show a similar impairment in fibrosis and smooth muscle accumulation. Blockade of LIGHT suppresses expression of lung TGF-β and IL-13, cytokines implicated in remodeling in humans, whereas exogenous administration of LIGHT to the airways induces fibrosis and smooth muscle hyperplasia; thus, LIGHT may be targeted to prevent asthma-related airway remodeling.

Shedding LIGHT on severe asthma

Moderate to severe asthma is difficult to treat because recurring bouts of inflammation in the lungs induce fibrosis, which reduces lung elasticity, gas exchange and responses to conventional therapy. A recent study identifies the tumor necrosis factor family member LIGHT as an essential mediator of airway fibrosis in a mouse model of chronic asthma (pages 596–603 ).

The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling

Individuals with chronic asthma show a progressive decline in lung function that is thought to be due to structural remodeling of the airways characterized by subepithelial fibrosis and smooth muscle hyperplasia. Here we show that the tumor necrosis factor (TNF) family member LIGHT is expressed on lung inflammatory cells after allergen exposure. Pharmacological inhibition of LIGHT using a fusion protein between the IgG Fc domain and lymphotoxin β receptor (LTβR) reduces lung fibrosis, smooth muscle hyperplasia and airway hyperresponsiveness in mouse models of chronic asthma, despite having little effect on airway eosinophilia. LIGHT-deficient mice also show a similar impairment in fibrosis and smooth muscle accumulation. Blockade of LIGHT suppresses expression of lung transforming growth factor-β (TGF-β) and interleukin-13 (IL-13), cytokines implicated in remodeling in humans, whereas exogenous administration of LIGHT to the airways induces fibrosis and smooth muscle hyperplasia, Thus, LIGHT may be targeted to prevent asthma-related airway remodeling.