Differential Expression of TRAIL and TRAIL Receptors in Allergic Asthmatics Following Segmental Antigen Challenge: Evidence for a Role of TRAIL in Eosinophil Survival

Abstract

Asthma is a chronic lung disease exhibiting airway obstruction, hyperresponsiveness, and inflammation, characterized by the infiltration of eosinophils into the airways and the underlying tissue. Prolonged eosinophilic inflammation depends on the balance between the cell’s inherent tendency to undergo apoptosis and the local eosinophil-viability enhancing activity. TRAIL, a member of the TNF family, induces apoptosis in most transformed cells; however, its role in health and disease remains unknown. To test the hypothesis that Ag-induced inflammation is associated with TRAIL/TRAIL-R interactions, we used a segmental Ag challenge (SAC) model in ragweed-allergic asthmatics and nonasthmatic patients and analyzed bronchoalveolar lavage (BAL) material for 2 wk. In asthmatic patients, the level of TRAIL in BAL fluid dramatically increased 24 h after SAC, which significantly correlated with BAL eosinophil counts. Immunohistochemical analysis of bronchial biopsies from asthmatic patients demonstrated that TRAIL staining was increased in epithelial, airway smooth muscle, and vascular smooth muscle cells and throughout the interstitial tissue after SAC. This was confirmed by quantitative immunocytochemical image analysis of BAL eosinophils and alveolar macrophages, which demonstrated that expression levels of TRAIL and DcR2 increased, whereas expression levels of the TRAIL-Rs DR4 and DR5 decreased in asthmatic subjects after SAC. We also determined that TRAIL prolongs eosinophil survival ex vivo. These data provide the first in vivo evidence that TRAIL expression is increased in asthmatics following Ag provocation and suggest that modulation of TRAIL and TRAIL-R interactions may play a crucial role in promoting eosinophil survival in asthma.

Airway Inflammation after Bronchial Thermoplasty for Severe Asthma

“…In a mouse model of asthma, increased expression of TRAIL was shown to be responsible for increased apoptosis of airway leukocytes and associated with the resolution of allergy through a reduction in Th2 production of IL-5 (51). In human asthma, a higher BAL eosinophil count is associated with a decreased expression of the canonical TRAIL death receptors (52). Conversely, TRAIL signaling has also been linked to nonapoptotic and proliferative events (52)(53)(54), thus indicating that further investigation into the role of TRAIL after BT is necessary to establish its function.…”

Non-canonical kinase signaling by the death ligand TRAIL in cancer cells: discord in the death receptor family

“…102 In addition, several other mechanisms have been reported to contribute to these effects of TRAIL, such as activation of NF-kB, insulin-like growth factor type 1 receptor (IGF1R) and SP-1. 103,104 Furthermore, TRAIL could stimulate p38-dependent INFg secretion and proliferation in T cells, 105 enhance survival signaling in eosinophils of asthma patients, 106 and stimulate ERK1/2 and Akt-dependent survival of fibroblast-like synoviocytes derived from rheumatoid arthritis patients. 107 Interestingly, also a role for TRAIL signaling has been found in the differentiation of different cell types.…”

The Tumor Necrosis Factor-A (TNF-A) Gene -308 G/A Polymorphism and the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (Trail) Gene Polymorphisms in Behcet'S Disease

“…Inflammation in BD is thought to be mediated by cytokines derived from T-helper type 1 lymphocytes, including TNF-α. Increased numbers of monocytes and T cells expressing gammadelta receptors produce extensive amounts of TNF-α, resulting in high levels of circulating TNF-α and soluble TNF receptors in the peripheral blood of the BD patients (15,16).The members of the TNF family play critical roles as prominent mediators of immune regulation and the inflammatory response (18). It was reported that TNF-α related polymorphisms could play an important role in the development of BD.…”