IL-33 promotes the induction and maintenance of Th2 immune responses by enhancing the function of OX40 ligand.
BACKGROUND
In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses.


METHODS
Purified human naïve or memory CD4+ T cells were stimulated with recombinant OX40L or TSLP-treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis.


RESULTS
IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2+ CD4+ Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase.


CONCLUSIONS
IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.
First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
Naoko
N
Murakami-Satsutani
First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
Tomoki
T
Ito
First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
Takahisa
T
Nakanishi
First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
Noriko
N
Inagaki
First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
Akihiro
A
Tanaka
First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
Phan Thi Xuan
PT
Vien
First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
Kayoko
K
Kibata
First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
Muneo
M
Inaba
First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
Shosaku
S
Nomura
D001249:Asthma / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D003876:Dermatitis, Atopic / Q000276:immunology*; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D058990:Molecular Targeted Therapy; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology*; D015854:Up-Regulation; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins; D000094632:Thymic Stromal Lymphopoietin