1 November 2012
IL-33, TH2, innate lymphoid cells, asthma, mammalian target of rapamycin, rapamycin, AHR, Airway hyperresponsiveness, APC, Allophycocyanin, BAL, Bronchoalveolar lavage, ICOS, Inducible costimulator, ILC, Innate lymphoid cell, Lin, Lineage-specific marker, mTOR(C1/2), Mammalian target of rapamycin (complex 1/2), PE, Phycoerythrin, PI3K, Phosphoinositide 3-kinase, rpS6, Ribosomal protein S6, S6K1, Ribosomal protein S6 kinase 1, TCR, T-cell receptor, TSLP, Thymic stromal lymphopoietin, WT, Wild-type
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 H2 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.
Our goal was to investigate a role for mammalian target of rapamycin (mTOR) signaling in the activation of T H2 and ILC responses and the induction of airway inflammation by IL-33.
We biochemically determined the effect of IL-33 on mTOR activation in T H2 cells and ILCs and examined the effect of this signaling pathway in vivo using a murine model of IL-33–induced lung inflammation.
We found that IL-33 induces mTOR activation through p110δ phosphoinositide 3-kinase and that blockade of the mTOR pathway inhibited IL-33–induced IL-5 and IL-13 production by T H2 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 wild-type 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.