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IL-28A (IFN-λ2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease.

Koltsida O, Hausding M, Stavropoulos A, Koch S, Tzelepis G, Ubel C, Kotenko SV, Sideras P, Lehr HA, Tepe M, Klucher KM, Doyle SE, Neurath MF, Finotto S, Andreakos E - EMBO Mol Med (2011)

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.

View Article: PubMed Central - PubMed

Affiliation: Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece.

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Related in: MedlinePlus

IL-28Rα-deficient mice develop increased Th2/Th17 responses and Th2/Th17-mediated allergic airway inflammationBALF differential counts of eosinophils and neutrophils expressed as mean ± SEM of 3–4 mice per group. One representative from three independent experiments is shown.BALF differential counts of lymphocytes expressed as mean ± SEM of 3–4 mice per group. One representative from three independent experiments is shown.Histological assessment of lung inflammation in IL-28Rα+/+ and IL-28Rα−/− mice. Hematoxylin and eosin stained lung sections and histological scoring expressed as mean values ± SEM from 5 to 7 mice per group are shown.Histological assessment of mucus secretion in IL-28Rα+/+ and IL-28Rα−/− mice. PAS stained sections and morphometric analysis expressed as mean values ± SEM from 5 to 7 mice per group are shown.Effector T cell responses in MLNs of OVA sensitized and challenged mice. Cytokine levels in supernatants of OVA-stimulated MLN cultures expressed as mean values ± SEM of seven mice per group from two independent experiments are shown.Increased total IgE levels in the serum of IL-28Rα−/− mice as compared to IL-28Rα+/+ littermates after OVA sensitization and challenge. Data represent mean values ± SEM.AHR measured as metacholine-induced increases of total lung resistance (RL) in mechanically ventilated IL-28Rα+/+ and IL-28Rα−/− mice. Data are expressed as mean values of percentage increase from baseline of the total RL ± SEM from 10 mice per group pooled from two independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001.
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fig03: IL-28Rα-deficient mice develop increased Th2/Th17 responses and Th2/Th17-mediated allergic airway inflammationBALF differential counts of eosinophils and neutrophils expressed as mean ± SEM of 3–4 mice per group. One representative from three independent experiments is shown.BALF differential counts of lymphocytes expressed as mean ± SEM of 3–4 mice per group. One representative from three independent experiments is shown.Histological assessment of lung inflammation in IL-28Rα+/+ and IL-28Rα−/− mice. Hematoxylin and eosin stained lung sections and histological scoring expressed as mean values ± SEM from 5 to 7 mice per group are shown.Histological assessment of mucus secretion in IL-28Rα+/+ and IL-28Rα−/− mice. PAS stained sections and morphometric analysis expressed as mean values ± SEM from 5 to 7 mice per group are shown.Effector T cell responses in MLNs of OVA sensitized and challenged mice. Cytokine levels in supernatants of OVA-stimulated MLN cultures expressed as mean values ± SEM of seven mice per group from two independent experiments are shown.Increased total IgE levels in the serum of IL-28Rα−/− mice as compared to IL-28Rα+/+ littermates after OVA sensitization and challenge. Data represent mean values ± SEM.AHR measured as metacholine-induced increases of total lung resistance (RL) in mechanically ventilated IL-28Rα+/+ and IL-28Rα−/− mice. Data are expressed as mean values of percentage increase from baseline of the total RL ± SEM from 10 mice per group pooled from two independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001.

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).


IL-28A (IFN-λ2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease.

Koltsida O, Hausding M, Stavropoulos A, Koch S, Tzelepis G, Ubel C, Kotenko SV, Sideras P, Lehr HA, Tepe M, Klucher KM, Doyle SE, Neurath MF, Finotto S, Andreakos E - EMBO Mol Med (2011)

IL-28Rα-deficient mice develop increased Th2/Th17 responses and Th2/Th17-mediated allergic airway inflammationBALF differential counts of eosinophils and neutrophils expressed as mean ± SEM of 3–4 mice per group. One representative from three independent experiments is shown.BALF differential counts of lymphocytes expressed as mean ± SEM of 3–4 mice per group. One representative from three independent experiments is shown.Histological assessment of lung inflammation in IL-28Rα+/+ and IL-28Rα−/− mice. Hematoxylin and eosin stained lung sections and histological scoring expressed as mean values ± SEM from 5 to 7 mice per group are shown.Histological assessment of mucus secretion in IL-28Rα+/+ and IL-28Rα−/− mice. PAS stained sections and morphometric analysis expressed as mean values ± SEM from 5 to 7 mice per group are shown.Effector T cell responses in MLNs of OVA sensitized and challenged mice. Cytokine levels in supernatants of OVA-stimulated MLN cultures expressed as mean values ± SEM of seven mice per group from two independent experiments are shown.Increased total IgE levels in the serum of IL-28Rα−/− mice as compared to IL-28Rα+/+ littermates after OVA sensitization and challenge. Data represent mean values ± SEM.AHR measured as metacholine-induced increases of total lung resistance (RL) in mechanically ventilated IL-28Rα+/+ and IL-28Rα−/− mice. Data are expressed as mean values of percentage increase from baseline of the total RL ± SEM from 10 mice per group pooled from two independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001.
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Related In: Results  -  Collection

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fig03: IL-28Rα-deficient mice develop increased Th2/Th17 responses and Th2/Th17-mediated allergic airway inflammationBALF differential counts of eosinophils and neutrophils expressed as mean ± SEM of 3–4 mice per group. One representative from three independent experiments is shown.BALF differential counts of lymphocytes expressed as mean ± SEM of 3–4 mice per group. One representative from three independent experiments is shown.Histological assessment of lung inflammation in IL-28Rα+/+ and IL-28Rα−/− mice. Hematoxylin and eosin stained lung sections and histological scoring expressed as mean values ± SEM from 5 to 7 mice per group are shown.Histological assessment of mucus secretion in IL-28Rα+/+ and IL-28Rα−/− mice. PAS stained sections and morphometric analysis expressed as mean values ± SEM from 5 to 7 mice per group are shown.Effector T cell responses in MLNs of OVA sensitized and challenged mice. Cytokine levels in supernatants of OVA-stimulated MLN cultures expressed as mean values ± SEM of seven mice per group from two independent experiments are shown.Increased total IgE levels in the serum of IL-28Rα−/− mice as compared to IL-28Rα+/+ littermates after OVA sensitization and challenge. Data represent mean values ± SEM.AHR measured as metacholine-induced increases of total lung resistance (RL) in mechanically ventilated IL-28Rα+/+ and IL-28Rα−/− mice. Data are expressed as mean values of percentage increase from baseline of the total RL ± SEM from 10 mice per group pooled from two independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece.

Show MeSH
Related in: MedlinePlus