Differential effects of the Toll-like receptor 2 agonists, PGN and Pam3CSK4 on anti-IgE induced human mast cell activation.

Yangyang Yu,Hang Yung Alaster Lau,Sze Wing Sam,Wei Zhang,Issan Yee San Tam,Chun Wai Ng,Kwok Ho Yip

doi:10.1371/journal.pone.0112989

Abstract

Mast cells are pivotal in the pathogenesis of allergy and inflammation. In addition to the classical IgE-dependent mechanism involving crosslinking of the high-affinity receptor for IgE (FcεRI), mast cells are also activated by Toll-like receptors (TLRs) which are at the center of innate immunity. In this study, we demonstrated that the response of LAD2 cells (a human mast cell line) to anti-IgE was altered in the presence of the TLR2 agonists peptidoglycan (PGN) and tripalmitoyl-S-glycero-Cys-(Lys)4 (Pam3CSK4). Pretreatment of PGN and Pam3CSK4 inhibited anti-IgE induced calcium mobilization and degranulation without down-regulation of FcεRI expression. Pam3CSK4 but not PGN acted in synergy with anti-IgE for IL-8 release when the TLR2 agonist was added simultaneously with anti-IgE. Studies with inhibitors of key enzymes implicated in mast cell signaling revealed that the synergistic release of IL-8 induced by Pam3CSK4 and anti-IgE involved ERK and calcineurin signaling cascades. The differential modulations of anti-IgE induced mast cell activation by PGN and Pam3CSK4 suggest that dimerization of TLR2 with TLR1 or TLR6 produced different modulating actions on FcεRI mediated human mast cell activation.

Highlights

Mast cells which express high-affinity IgE receptor (FceRI) are key immune effector cells in allergic associated diseases such as asthma and atopic dermatitis
The contrasting observations may be due to the nature of the pathogenic molecules expressed by the microbes as implicated in the current study which demonstrated that TLR2/1 and TLR2/6 ligands could differentially modulate FceRI mediated response in human mast cells
We showed that TLR2 ligands differentially modify human mast cell functions in response to antigen through inhibiting the degranulation and enhancing the release of de novo synthesized mediators

Summary

Introduction

Mast cells which express high-affinity IgE receptor (FceRI) are key immune effector cells in allergic associated diseases such as asthma and atopic dermatitis. Other groups have reported inhibitory effects on mast cell degranulation and cytokines production which were either through decreased FceRI expression or suppression of calcium mobilization and Erk phosphorylation due to pre-treatment with different TLR2 ligands [1,2,8]. Most of these studies were carried out by investigating mouse mast cells. One study used the human mast cells line LAD2 cells and observed the suppression of FceRI expression and antigen-induced mast cells degranulation upon TLR2 ligands pretreatment [2]. The modulatory effects of TLR2 on FceRI -induced release of de novo synthesized mediators from human mast cells are unclear

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Conclusion