Airway hyperreactivity (AHR), eosinophilic inflammation with a Th2-type cytokine profile, and specific Th2-mediated IgE production characterize allergic asthma. In this paper, we show that OVA-immunized Jα18−/− mice, which are exclusively deficient in the invariant Vα14+ (iVα14), CD1d-restricted NKT cells, exhibit impaired AHR and airway eosinophilia, decreased IL-4 and IL-5 production in bronchoalveolar lavage fluid, and reduced OVA-specific IgE compared with wild-type (WT) littermates. Adoptive transfer of WT iVα14 NKT cells fully reconstitutes the capacity of Jα18−/− mice to develop allergic asthma. Also, specific tetramer staining shows that OVA-immunized WT mice have activated (CD69+) iVα14 NKT cells. Importantly, anti-CD1d mAb treatment blocked the ability of iVα14 T cells to amplify eosinophil recruitment to airways, and both Th2 cytokine and IgE production following OVA challenge. In conclusion, these findings clearly demonstrate that iVα14 NKT cells are required to participate in allergen-induced Th2 airway inflammation through a CD1d-dependent mechanism.

Interleukin-33 (IL-33), the most recently identified member of the IL-1 family, induces synthesis of T Helper 2 (Th2)-type cytokines via its heterodimeric ST2/IL-1RAcP receptor. Th2-type cytokines play an important role in fibrosis; thus, we investigated the role of IL-33 in liver fibrosis. IL-33, ST2 and IL-1RAcP gene expression was analysed in mouse and human normal (n= 6) and fibrotic livers (n= 28), and in human hepatocellular carcinoma (HCC; n= 22), using real-time PCR. IL-33 protein was detected in normal and fibrotic liver sections and in isolated liver cells using Western blotting and immunolocalization approaches. Our results showed that IL-33 and ST2 mRNA was overproduced in mouse and human fibrotic livers, but not in human HCC. IL-33 expression correlated with ST2 expression and also with collagen expression in fibrotic livers. The major sources of IL-33 in normal liver from both mice and human beings are the liver sinusoidal endothelial cells and, in fibrotic liver, the activated hepatic stellate cells (HSC). Moreover, IL-33 expression was increased in cultured HSC when stimulated by pro-inflammatory cytokines. In conclusion, IL-33 is strongly associated with fibrosis in chronic liver injury and activated HSC are a source of IL-33.

Allergic asthma is a multifaceted syndrome consisting of eosinophil‐rich airway inflammation, bronchospasm, and airway hyper‐responsiveness (AHR). Using a mouse model of allergic asthma, we previously reported that invariant NKT (iNKT) cells increase the severity of this disease. Herein, we demonstrate that a single i.v. injection of α‐galactosylceramide (α‐GalCer), 1 h before the first airway allergen challenge of OVA‐sensitized mice, abrogates elicitation of AHR, airway eosinophilia, IL‐4 and IL‐5 production in bronchoalveolar lavage fluid, and specific anti‐OVA IgE antibodies. Further, α‐GalCer administered intranasally also strongly inhibited the major symptoms of asthma in sensitized and challenged mice. α‐GalCer treatment induces iNKT cell accumulation in the lungs, and shifts their cytokine profile from pro‐asthmatic IL‐4 to a protective IFN‐γ production. The role of IFN‐γ from iNKT cells in protection was shown by adoptive transfer of sorted iNKT cells from OVA‐sensitized and α‐GalCer‐treated mice which protected immunized recipients from manifesting asthma by an IFN‐γ‐dependent pathway. Our findings demonstrate for the first time that α‐GalCer administered locally inhibits asthma symptoms, even in predisposed asthmatic mice, through an iNKT cell‐ and IFN‐γ‐dependent pathway. See accompanying commentary: