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Role of Tyk-2 in Th9 and Th17 cells in allergic asthma.

Übel C, Graser A, Koch S, Rieker RJ, Lehr HA, Müller M, Finotto S - Sci Rep (2014)

Bottom Line: In a murine model of allergic asthma, we found that Tyk-2((-/-)) asthmatic mice have induced peribronchial collagen deposition, mucosal type mast cells in the lung, IRF4 and hyperproliferative lung Th2 CD4(+) effector T cells over-expressing IL-3, IL-4, IL-5, IL-10 and IL-13.We also observed increased Th9 cells expressing IL-9 and IL-10 as well as T helper cells expressing IL-6, IL-10 and IL-21 with a defect in IL-17A and IL-17F production.Finally, in vivo treatment with rIL-17A inhibited local CD4(+)CD25(+)Foxp3(+) T regulatory cells as well as Th2 cytokines without affecting IL-9 in the lung.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Pneumology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany [2].

ABSTRACT
In a murine model of allergic asthma, we found that Tyk-2((-/-)) asthmatic mice have induced peribronchial collagen deposition, mucosal type mast cells in the lung, IRF4 and hyperproliferative lung Th2 CD4(+) effector T cells over-expressing IL-3, IL-4, IL-5, IL-10 and IL-13. We also observed increased Th9 cells expressing IL-9 and IL-10 as well as T helper cells expressing IL-6, IL-10 and IL-21 with a defect in IL-17A and IL-17F production. This T helper phenotype was accompanied by increased SOCS3 in the lung of Tyk-2 deficient asthmatic mice. Finally, in vivo treatment with rIL-17A inhibited local CD4(+)CD25(+)Foxp3(+) T regulatory cells as well as Th2 cytokines without affecting IL-9 in the lung. These results suggest a role of Tyk-2 in different subsets of T helper cells mediated by SOCS3 regulation that is relevant for the treatment of asthma, cancer and autoimmune diseases.

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Tyk-2(−/−) mice showed a defective Th17 cytokine production in vivo.(a). and (b). Mice were treated with OVA as described in the methods section. After 21 days the mice were sacrificed and total cells were isolated from the lung. After 24 h incubation with antibodies against CD3 and CD28 supernatants were analyzed by ELISA for IL-17A ((a): n = 2–4, p = 0,041; p = 0,007) and IL-17F ((b): n = 2–4, p = 0,046, p = 0,046). (c). Total lung cells from untreated mice were isolated and incubated with antibodies against CD4 and IL-17A and analyzed by flow cytometry. Data show on the one hand, lung IL-17A+CD4+ T cells (left panel n = 3–4, p = 0,0003) and on the other hand lung IL-17A+CD4− cells (right panel n = 3–4, p = 0,003). (d). Total lung cells from naïve and allergen-treated mice were incubated with α-CD3 and α-CD28 antibodies for 24 h and analyzed by ELISA for IL-1β production (n = 2–4, p = 0,009). (e). and (f). IL-21(n = 4–5, p = 0,025; p = 0,0019; p = 0,041; p = 0,002) and IL-23 (n = 3–5, p = 0,045; p = 0,038; p = 0,043; p = 0,012) levels were measured in the BALF of naïve and asthmatic mice.
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f3: Tyk-2(−/−) mice showed a defective Th17 cytokine production in vivo.(a). and (b). Mice were treated with OVA as described in the methods section. After 21 days the mice were sacrificed and total cells were isolated from the lung. After 24 h incubation with antibodies against CD3 and CD28 supernatants were analyzed by ELISA for IL-17A ((a): n = 2–4, p = 0,041; p = 0,007) and IL-17F ((b): n = 2–4, p = 0,046, p = 0,046). (c). Total lung cells from untreated mice were isolated and incubated with antibodies against CD4 and IL-17A and analyzed by flow cytometry. Data show on the one hand, lung IL-17A+CD4+ T cells (left panel n = 3–4, p = 0,0003) and on the other hand lung IL-17A+CD4− cells (right panel n = 3–4, p = 0,003). (d). Total lung cells from naïve and allergen-treated mice were incubated with α-CD3 and α-CD28 antibodies for 24 h and analyzed by ELISA for IL-1β production (n = 2–4, p = 0,009). (e). and (f). IL-21(n = 4–5, p = 0,025; p = 0,0019; p = 0,041; p = 0,002) and IL-23 (n = 3–5, p = 0,045; p = 0,038; p = 0,043; p = 0,012) levels were measured in the BALF of naïve and asthmatic mice.

Mentions: We next analyzed IL-17A and IL-17F levels which we found to be down-regulated in Tyk-2(−/−) mice after allergen challenge (Fig. 3a, b) as well as in naïve mice (Fig. 3c) compared to wild-type mice.


Role of Tyk-2 in Th9 and Th17 cells in allergic asthma.

Übel C, Graser A, Koch S, Rieker RJ, Lehr HA, Müller M, Finotto S - Sci Rep (2014)

Tyk-2(−/−) mice showed a defective Th17 cytokine production in vivo.(a). and (b). Mice were treated with OVA as described in the methods section. After 21 days the mice were sacrificed and total cells were isolated from the lung. After 24 h incubation with antibodies against CD3 and CD28 supernatants were analyzed by ELISA for IL-17A ((a): n = 2–4, p = 0,041; p = 0,007) and IL-17F ((b): n = 2–4, p = 0,046, p = 0,046). (c). Total lung cells from untreated mice were isolated and incubated with antibodies against CD4 and IL-17A and analyzed by flow cytometry. Data show on the one hand, lung IL-17A+CD4+ T cells (left panel n = 3–4, p = 0,0003) and on the other hand lung IL-17A+CD4− cells (right panel n = 3–4, p = 0,003). (d). Total lung cells from naïve and allergen-treated mice were incubated with α-CD3 and α-CD28 antibodies for 24 h and analyzed by ELISA for IL-1β production (n = 2–4, p = 0,009). (e). and (f). IL-21(n = 4–5, p = 0,025; p = 0,0019; p = 0,041; p = 0,002) and IL-23 (n = 3–5, p = 0,045; p = 0,038; p = 0,043; p = 0,012) levels were measured in the BALF of naïve and asthmatic mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127519&req=5

f3: Tyk-2(−/−) mice showed a defective Th17 cytokine production in vivo.(a). and (b). Mice were treated with OVA as described in the methods section. After 21 days the mice were sacrificed and total cells were isolated from the lung. After 24 h incubation with antibodies against CD3 and CD28 supernatants were analyzed by ELISA for IL-17A ((a): n = 2–4, p = 0,041; p = 0,007) and IL-17F ((b): n = 2–4, p = 0,046, p = 0,046). (c). Total lung cells from untreated mice were isolated and incubated with antibodies against CD4 and IL-17A and analyzed by flow cytometry. Data show on the one hand, lung IL-17A+CD4+ T cells (left panel n = 3–4, p = 0,0003) and on the other hand lung IL-17A+CD4− cells (right panel n = 3–4, p = 0,003). (d). Total lung cells from naïve and allergen-treated mice were incubated with α-CD3 and α-CD28 antibodies for 24 h and analyzed by ELISA for IL-1β production (n = 2–4, p = 0,009). (e). and (f). IL-21(n = 4–5, p = 0,025; p = 0,0019; p = 0,041; p = 0,002) and IL-23 (n = 3–5, p = 0,045; p = 0,038; p = 0,043; p = 0,012) levels were measured in the BALF of naïve and asthmatic mice.
Mentions: We next analyzed IL-17A and IL-17F levels which we found to be down-regulated in Tyk-2(−/−) mice after allergen challenge (Fig. 3a, b) as well as in naïve mice (Fig. 3c) compared to wild-type mice.

Bottom Line: In a murine model of allergic asthma, we found that Tyk-2((-/-)) asthmatic mice have induced peribronchial collagen deposition, mucosal type mast cells in the lung, IRF4 and hyperproliferative lung Th2 CD4(+) effector T cells over-expressing IL-3, IL-4, IL-5, IL-10 and IL-13.We also observed increased Th9 cells expressing IL-9 and IL-10 as well as T helper cells expressing IL-6, IL-10 and IL-21 with a defect in IL-17A and IL-17F production.Finally, in vivo treatment with rIL-17A inhibited local CD4(+)CD25(+)Foxp3(+) T regulatory cells as well as Th2 cytokines without affecting IL-9 in the lung.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Pneumology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany [2].

ABSTRACT
In a murine model of allergic asthma, we found that Tyk-2((-/-)) asthmatic mice have induced peribronchial collagen deposition, mucosal type mast cells in the lung, IRF4 and hyperproliferative lung Th2 CD4(+) effector T cells over-expressing IL-3, IL-4, IL-5, IL-10 and IL-13. We also observed increased Th9 cells expressing IL-9 and IL-10 as well as T helper cells expressing IL-6, IL-10 and IL-21 with a defect in IL-17A and IL-17F production. This T helper phenotype was accompanied by increased SOCS3 in the lung of Tyk-2 deficient asthmatic mice. Finally, in vivo treatment with rIL-17A inhibited local CD4(+)CD25(+)Foxp3(+) T regulatory cells as well as Th2 cytokines without affecting IL-9 in the lung. These results suggest a role of Tyk-2 in different subsets of T helper cells mediated by SOCS3 regulation that is relevant for the treatment of asthma, cancer and autoimmune diseases.

Show MeSH
Related in: MedlinePlus