Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function

Abstract

In a mouse experimental asthma model, the administration of bacterial lipopolysaccharide (LPS), particularly at low doses, enhances the levels of ovalbumin (OVA)-induced eosinophilic airway inflammation. In an effort to clarify the cellular and molecular basis for the LPS effect, we demonstrate that the OVA-induced eosinophilic inflammation in the lung is dramatically increased by the administration of LPS in wild-type mice, whereas such increase was not observed in mast-cell-deficient mice or Toll-like receptor (TLR)4-deficient mice. Adoptive transfer of bone-marrow-derived mast cells (BMMCs) from wild-type, but not from TLR4-deficient, mice restored the increased eosinophilic inflammation in mast-celldeficient mice. Wild-type BMMCs pretreated with LPS in vitro also reconstituted the eosinophilic inflammation. Moreover, in vitro analysis revealed that the treatment of BMMCs with LPS resulted in NF-B activation, sustained up-regulation of GATA1 and -2 expression, and increased the capability to produce IL-5 and -13. Dramatic increases in the expression of IL-5 and -13 and Eotaxin 2 were detected in LPS-treated BMMCs after costimulation with LPS and IgE͞Ag. Overexpression of GATA1, but not GATA2, in MC9 mast cells resulted in increased transcriptional activity of IL-4, -5, and -13. Furthermore, the levels of transcription of Th2 cytokines in BMMCs were decreased by the introduction of small interfering RNA for GATA1. Thus, mast cells appear to control allergic airway inflammation after their activation and modulation through TLR4-mediated induction of GATA1 and subsequent increase in Th2 cytokine production.cytokine ͉ GATA1 ͉ mast cell ͉ lipopolysaccharide ͉ bone-marrow-derived mast cells

Progress in Allergy Signal Research on Mast Cells: Regulation of Allergic Airway Inflammation Through Toll-Like Receptor 4–Mediated Modification of Mast Cell Function

“…BMMCs prepared from wild type (+/ +) or TLR4 KO mice were transferred into W / W v mice. As anticipated, the levels of eosinophilic infiltration were enhanced by the administration of +/ + BMMCs but not of TLR4 KO BMMCs (21). Collectively, these results clearly indicate that TLR4 on mast cells play a critical role in low dose LPS-mediated enhancement of airway eosinophilic inflammation.…”

“…Therefore, the changes in the expression levels of protein expression of GATA1 and GATA2 were examined in BMMCs treated with LPS. The levels of GATA1 and GATA2 but not GATA3 were substantially increased in the BMMCs after LPS treatment (21). The LPS-induced increase in the levels of GATA1 and GATA2 protein was not detected in TLR4 KO BMMCs.…”

“…The levels of IL-5, IL-13, and Eotaxin-2 were substantially increased after LPS treatment, whereas the production of IL-6 and TNF-α was only slightly increased (21).…”

“…Bone marrow-derived mast cells (BMMCs) were generated by culturing bone marrow cells with IL-3 for four weeks. The administration of +/ + BMMCs resulted in the dramatic eosinophilic infiltration in the BAL fluid of W / W v mice immunized OVA and LPS when compared to mice not given wild type (+/ +) BMMCs (21). No apparent affect was observed in the numbers of macrophages, neutrophils, and lymphocytes with the +/ + BMMC transfer.…”

“…In this review, we introduced our recent work describing the role of TLR4 on mast cells in allergic airway inflammation and in the production of Th2 cytokines, which may help explain the enhancement of allergic eosinophilic airway inflammation by LPS (21). From our studies presented here, we propose a new mechanism whereby mast cells play a crucial role for regulating eosinophilic airway inflammation.…”