Interaction of Der p 2 with Toll-like Receptor 4 and its Effect on Cytokine Secretion

Abstract

Der p 2, which is a major allergen of house dust mite, plays an important role in the pathogenesis of allergic disease. There is controversy regarding whether Der p 2 binds to Toll-like receptor 4 (TLR4), and its inflammatory effect has not yet been elucidated. In the current study, we examined the interaction of Der p 2 with TLR4 and the effect of Der p 2 on cytokine release in THP-1 cells and lymphocytes. Among house dust mite extracts, recombinant TLR4 protein interacted with Der p 2. The overall structure of Der p 2 is characteristic of the immunoglobulin superfamily and contains ten β-strands, forming a β-cup fold with two anti-parallel β-sheets, and a short 3 10 helix. The two sheets can be separated, further allowing the formation of a large internal pocket, which is narrow and suitable for binding large flat molecules such as lipid-like molecules. Der p 2 caused increased secretion of IL-6, IL-8, and MCP-1, which are neutrophil survival factors, in human monocytic THP-1 cells in a time-dependent manner. Der p 2 also induces the release of cytokines in normal and allergic lymphocytes. Supernatant after treatment with Der p 2 inhibited neutrophil apoptosis. In coculture of lymphocytes with neutrophils, Der p 2 inhibited spontaneous apoptosis of allergic neutrophils. In summary, Der p 2 binds to TLR4 and induces an inflammatory response such as cytokine secretion in immune cells. These findings may enable elucidation of allergy pathogenesis by specific allergen of house dust mite.

Lycopene Inhibits Toll-Like Receptor 4-Mediated Expression of Inflammatory Cytokines in House Dust Mite-Stimulated Respiratory Epithelial Cells

“…Additionally, HDM increased TLR 4-mediated infiltration of eosinophils and neutrophils into the lungs of mice [ 47 ]. The HDM allergen Derp 2 activated TLR4 and induced IL-6, IL-8, and MCP-1 in THP-1 cells and lymphocytes [ 48 ]. These studies demonstrate the relationship between TLR4 and cytokine expression in HDM-stimulated cells.…”

Are the Terms Major and Minor Allergens Useful for Precision Allergology?

“…Innate immune pathways activation by non-protease allergens has been an important advance in allergen characterization. The first report showing this type of mechanism was the ability of Der p 2 to activate pro-inflammatory signals through TLR-4 in bronchial epithelial cells (17), a report followed by other effects of this allergen (18)(19)(20)(21)(22). Among other HDM allergens that can induce non-IgE mediated proinflammatory activation of bronchial epithelium are Der p 5 (23), Der p 13 (24), and Blo t 7 (25).…”

Co-Activation of Human Whole Blood Cells with Lipopolysaccharides and an Allergen

“…The cell response to Der p 2 triggers the activation of the NF-κB and MAPK signaling pathways, which regulate the synthesis of inflammation intermediators in different manners [ 34 ]. Model studies on THP-1 cell cultures [ 3 ], as well as on isolated neutrophils and B-lymphocytes [ 12 ], showed that Der p 2 effectively promotes isolated cells to produce IL-6, IL-1, IL-8, CXCL10, and TNF-α. The isolated B-cells of blood also react to the allergen Der p 2 via the production of pro-inflammatory cytokines [ 35 ].…”

“…A study on transfected HEK MD-2293FT cells showed that, similar to LPS, Der p 2 is able to induce the dimerization of TLR4 and the activation of intracellular signaling pathways, leading to the synthesis of pro-inflammatory cytokines and chemokines, and it can increase LPS-induced TLR4-dependent responses [ 3 ]. Der p 2 causes the elevated secretion of IL-6 and IL-8 cytokines by THP-1 monocytes and B-lymphocytes via the activation of TLR4 and MAPK [ 12 ]. LPS and Der p 2 demonstrated synergistic effects on IL-8 and IL-6 produced by BEAS2B lung cell lines.…”