Lipopolysaccharide/TLR4 stimulates IL-13 production through a MyD88-BLT2-linked cascade in mast cells, potentially contributing to the allergic response

A. Jin Lee, Myungja Ro, Kyung Jin Cho, Jae-Hong Kim

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

In an experimental asthma model, the activation of TLR4 by bacterial LPS occasionally exacerbates allergic inflammation through the production of Th2 cytokines, and mast cells have been suggested to play a central role in this response. However, the detailed mechanism underlying how LPS/TLR4 stimulates the production of Th2 cytokines, especially IL-13, remains unclear in mast cells. In the current study, we observed that the expression levels of leukotriene B4 receptor-2 (BLT2) and the synthesis of its ligands were highly upregulated in LPS-stimulated bone marrow-derived mast cells and that BLT2 blockade with small interfering RNA or a pharmacological inhibitor completely abolished IL-13 production, suggesting a mediatory role of the BLT2 ligand-BLT2 axis in LPS/TLR4 signaling to IL-13 synthesis in mast cells. Moreover, we demonstrated that MyD88 lies upstream of the BLT2 ligand-BLT2 axis and that this MyD88-BLT2 cascade leads to the generation of reactive oxygen species through NADPH oxidase 1 and the subsequent activation of NF-kB, thereby mediating IL-13 synthesis. Interestingly, we observed that costimulation of LPS/ TLR4 and IgE/FcRI caused greatly enhanced IL-13 synthesis in mast cells, and blockading BLT2 abolished these effects. Similarly, in vivo, the IL-13 level was markedly enhanced by LPS administration in an OVA-induced asthma model, and injecting a BLT2 antagonist beforehand clearly attenuated this increase. Together, our findings suggest that a BLT2-linked cascade plays a pivotal role in LPS/TLR4 signaling for IL-13 synthesis in mast cells, thereby potentially exacerbating allergic response. Our findings may provide insight into the mechanisms underlying how bacterial infection worsens allergic inflammation under certain conditions.

Original languageEnglish
Pages (from-to)409-417
Number of pages9
JournalJournal of Immunology
Volume199
Issue number2
DOIs
Publication statusPublished - 2017 Jul 15

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Interleukin-13
Mast Cells
Lipopolysaccharides
Ligands
Asthma
Leukotriene B4 Receptors
Cytokines
Inflammation
Th2 Cells
NF-kappa B
Bacterial Infections
Immunoglobulin E
Small Interfering RNA
Reactive Oxygen Species
Theoretical Models
Bone Marrow
Pharmacology

ASJC Scopus subject areas

  • Immunology

Cite this

Lipopolysaccharide/TLR4 stimulates IL-13 production through a MyD88-BLT2-linked cascade in mast cells, potentially contributing to the allergic response. / Lee, A. Jin; Ro, Myungja; Cho, Kyung Jin; Kim, Jae-Hong.

In: Journal of Immunology, Vol. 199, No. 2, 15.07.2017, p. 409-417.

Research output: Contribution to journalArticle

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abstract = "In an experimental asthma model, the activation of TLR4 by bacterial LPS occasionally exacerbates allergic inflammation through the production of Th2 cytokines, and mast cells have been suggested to play a central role in this response. However, the detailed mechanism underlying how LPS/TLR4 stimulates the production of Th2 cytokines, especially IL-13, remains unclear in mast cells. In the current study, we observed that the expression levels of leukotriene B4 receptor-2 (BLT2) and the synthesis of its ligands were highly upregulated in LPS-stimulated bone marrow-derived mast cells and that BLT2 blockade with small interfering RNA or a pharmacological inhibitor completely abolished IL-13 production, suggesting a mediatory role of the BLT2 ligand-BLT2 axis in LPS/TLR4 signaling to IL-13 synthesis in mast cells. Moreover, we demonstrated that MyD88 lies upstream of the BLT2 ligand-BLT2 axis and that this MyD88-BLT2 cascade leads to the generation of reactive oxygen species through NADPH oxidase 1 and the subsequent activation of NF-kB, thereby mediating IL-13 synthesis. Interestingly, we observed that costimulation of LPS/ TLR4 and IgE/FcRI caused greatly enhanced IL-13 synthesis in mast cells, and blockading BLT2 abolished these effects. Similarly, in vivo, the IL-13 level was markedly enhanced by LPS administration in an OVA-induced asthma model, and injecting a BLT2 antagonist beforehand clearly attenuated this increase. Together, our findings suggest that a BLT2-linked cascade plays a pivotal role in LPS/TLR4 signaling for IL-13 synthesis in mast cells, thereby potentially exacerbating allergic response. Our findings may provide insight into the mechanisms underlying how bacterial infection worsens allergic inflammation under certain conditions.",
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