IL-28A (IFN-λ2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease.
Bottom Line: IL-28 (IFN-λ) cytokines exhibit potent antiviral and antitumor function but their full spectrum of activities remains largely unknown.Recently, IL-28 cytokine family members were found to be profoundly down-regulated in allergic asthma.Central to IL-28A immunoregulatory activity was its capacity to modulate lung CD11c(+) dendritic cell (DC) function to down-regulate OX40L, up-regulate IL-12p70 and promote Th1 differentiation.
Affiliation: Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece.Show MeSH
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Mentions: To explore the role of endogenous IL-28 cytokine production in allergic airway disease, we took advantage of mice in which the IL-28RA gene encoding the alpha chain of the IL-28 receptor complex has been inactivated by homologous recombination (Ank et al, 2008). Using the OVA model of allergic airway inflammation (Fig 1A), we found that OVA-sensitized and -challenged IL-28Rα−/− mice exhibited a significant increase in eosinophilic cell infiltration in the BALF as compared to wild-type controls (Fig 3A, left panel). Although eosinophils constituted the main infiltrating cell population in the lung, an increase in neutrophils (Fig 3A, right panel) and a tendency for increased lymphocytes (Fig 3B) was also observed in IL-28Rα−/− mice. This was further accompanied by significantly enhanced inflammatory infiltrates in the lung (Fig 3C) and goblet cell metaplasia in the airways (Fig 3D) of IL-28Rα−/− mice. Notably, effector Th2 and Th17 cell responses against OVA were also increased in IL-28Rα−/− mice. MLN cells from IL-28Rα−/− mice exhibited significantly higher levels of IL-5, IL-13 and IL-17 than their wild-type counterparts whereas IFN-γ levels were very low, due to the strong Th2 skewing of this model, and not affected (Fig 3E). Similar observations were also made when CD4+ T cells from the lung of IL-28Rα−/− mice were analysed (Supporting Information Fig S2A–C). Although IL-4 was not detectable in MLN cultures, it was readily produced in CD4+ T cell cultures from the lung and significantly up-regulated in IL-28Rα−/− mice (Supporting Information Fig S2A). Finally, IL-28Rα−/− mice exhibited increased IgE levels in the serum compared to wild-type controls (Fig 3F).
Affiliation: Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece.