期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 130, 期 5, 页码 1159-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2012.05.018
关键词
IL-33; T(H)2; innate lymphoid cells; asthma; mammalian target of rapamycin; rapamycin
资金
- Wellcome Trust
- MRC
- Medical Research Council Clinical Training fellowship
- MRC [G9818261, G0801198, G0902003] Funding Source: UKRI
- Medical Research Council [G0902003, G0801198, G9818261] Funding Source: researchfish
Background: The IL-1 family cytokine IL-33 is involved in the induction of airway inflammation in allergic patients and after viral infection. Several cell types, including CD4(+) T(H)2 cells and the recently described type 2 innate lymphoid cells (ILCs), are targets for IL-33, yet the mechanisms by which this cytokine modulates their activation are not clear. Objectives: Our goal was to investigate a role for mammalian target of rapamycin (mTOR) signaling in the activation of T(H)2 and ILC responses and the induction of airway inflammation by IL-33. Methods: We biochemically determined the effect of IL-33 on mTOR activation in T(H)2 cells and ILCs and examined the effect of this signaling pathway in vivo using a murine model of IL-33-induced lung inflammation. Results: We found that IL-33 induces mTOR activation through p110 delta phosphoinositide 3-kinase and that blockade of the mTOR pathway inhibited IL-33-induced IL-5 and IL-13 production by T(H)2 cells and ILCs. Furthermore, use of a ribosomal protein S6 kinase 1 inhibitor implicated a role for ribosomal protein S6 kinase 1 in IL-33-induced mTOR-dependent cytokine production. Intranasal administration of IL-33 to wild-type mice induced airway inflammation, whereas adoptive transfer of wildtype ILCs to IL-33 receptor-deficient (St2(-/-)) mice recapitulated this response. Importantly, coadministration of the mTOR inhibitor rapamycin reduced IL-33-dependent ILC, macrophage, and eosinophil accumulation; cytokine secretion; and mucus deposition in the airways. Conclusion: These data reveal a hitherto unrecognized role of mTOR signaling in IL-33-driven, ILC-dependent inflammation in vivo and suggest that manipulation of this pathway might represent a target for therapeutic intervention for airway inflammation. (J Allergy Clin Immunol 2012;130:1159-66.)
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