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γ-Secretase Inhibitor Alleviates Acute Airway Inflammation of Allergic Asthma in Mice by Downregulating Th17 Cell Differentiation.

Zhang W, Zhang X, Sheng A, Weng C, Zhu T, Zhao W, Li C - Mediators Inflamm. (2015)

Bottom Line: Th17 cell differentiation requires Notch signaling. γ-Secretase inhibitor (GSI) blocks Notch signaling; thus, it may be considered as a potential treatment for allergic asthma.GSI ameliorated the development of OVA-induced asthma, including suppressing airway inflammation responses and reducing the severity of clinical signs.GSI also significantly suppressed Th17-cell responses in spleen and reduced IL-17 levels in serum.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Pulmonology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou, Zhejiang 325027, China.

ABSTRACT
T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. Th17 cell differentiation requires Notch signaling. γ-Secretase inhibitor (GSI) blocks Notch signaling; thus, it may be considered as a potential treatment for allergic asthma. The aim of this study was to evaluate the effect of GSI on Th17 cell differentiation in a mouse model of allergic asthma. OVA was used to induce mouse asthma model in the presence and absence of GSI. GSI ameliorated the development of OVA-induced asthma, including suppressing airway inflammation responses and reducing the severity of clinical signs. GSI also significantly suppressed Th17-cell responses in spleen and reduced IL-17 levels in serum. These findings suggest that GSI directly regulates Th17 responses through a Notch signaling-dependent pathway in mouse model of allergic asthma, supporting the notion that GSI is a potential therapeutic agent for the treatment of allergic asthma.

No MeSH data available.


Related in: MedlinePlus

GSI decreased Notch1 and NICD. BALB/C mice were sensitized i.p. with OVA and challenged with OVA in the presence and absence of GSI. (a) The expression of Notch1 mRNA was evaluated by quantitative real-time RT-PCR. GAPDH was used as internal control. (b) Protein levels of NICD were examined by Western blotting. β-actin was used as a loading control. (A) Sham group; (B) OVA + DMSO; (C) OVA + GSI. Data expressed as Mean ± SEM. N = 8 mice per group. ∗P < 0.01 compared with the sham group. #P < 0.01 compared with the vehicle group.
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fig3: GSI decreased Notch1 and NICD. BALB/C mice were sensitized i.p. with OVA and challenged with OVA in the presence and absence of GSI. (a) The expression of Notch1 mRNA was evaluated by quantitative real-time RT-PCR. GAPDH was used as internal control. (b) Protein levels of NICD were examined by Western blotting. β-actin was used as a loading control. (A) Sham group; (B) OVA + DMSO; (C) OVA + GSI. Data expressed as Mean ± SEM. N = 8 mice per group. ∗P < 0.01 compared with the sham group. #P < 0.01 compared with the vehicle group.

Mentions: To investigate the blockage effects of GSI on Notch signaling, mRNA expression of Notch1, a receptor of Notch signaling, was examined. As shown in Figure 3(a), OVA-challenged mice revealed enhanced Notch1 mRNA expression, as compared with the sham group (1.31 ± 0.13 versus 0.84 ± 0.13, P < 0.01). On the other hand, GSI treatment led to the reduction of Notch1 mRNA expression (0.92 ± 0.088  P < 0.01 comparing to OVA group). Consistent with this observation, OVA-challenged mice revealed increased NICD generation as compared to sham group (0.18 ± 0.02 versus 0.09 ± 0.01, P < 0.01). GSI treatment decreased NICD generation (0.06 ± 0.03) comparing to OVA group (Figure 3(b), P < 0.01). Results presented here suggest that GSI can effectively block Notch signaling.


γ-Secretase Inhibitor Alleviates Acute Airway Inflammation of Allergic Asthma in Mice by Downregulating Th17 Cell Differentiation.

Zhang W, Zhang X, Sheng A, Weng C, Zhu T, Zhao W, Li C - Mediators Inflamm. (2015)

GSI decreased Notch1 and NICD. BALB/C mice were sensitized i.p. with OVA and challenged with OVA in the presence and absence of GSI. (a) The expression of Notch1 mRNA was evaluated by quantitative real-time RT-PCR. GAPDH was used as internal control. (b) Protein levels of NICD were examined by Western blotting. β-actin was used as a loading control. (A) Sham group; (B) OVA + DMSO; (C) OVA + GSI. Data expressed as Mean ± SEM. N = 8 mice per group. ∗P < 0.01 compared with the sham group. #P < 0.01 compared with the vehicle group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: GSI decreased Notch1 and NICD. BALB/C mice were sensitized i.p. with OVA and challenged with OVA in the presence and absence of GSI. (a) The expression of Notch1 mRNA was evaluated by quantitative real-time RT-PCR. GAPDH was used as internal control. (b) Protein levels of NICD were examined by Western blotting. β-actin was used as a loading control. (A) Sham group; (B) OVA + DMSO; (C) OVA + GSI. Data expressed as Mean ± SEM. N = 8 mice per group. ∗P < 0.01 compared with the sham group. #P < 0.01 compared with the vehicle group.
Mentions: To investigate the blockage effects of GSI on Notch signaling, mRNA expression of Notch1, a receptor of Notch signaling, was examined. As shown in Figure 3(a), OVA-challenged mice revealed enhanced Notch1 mRNA expression, as compared with the sham group (1.31 ± 0.13 versus 0.84 ± 0.13, P < 0.01). On the other hand, GSI treatment led to the reduction of Notch1 mRNA expression (0.92 ± 0.088  P < 0.01 comparing to OVA group). Consistent with this observation, OVA-challenged mice revealed increased NICD generation as compared to sham group (0.18 ± 0.02 versus 0.09 ± 0.01, P < 0.01). GSI treatment decreased NICD generation (0.06 ± 0.03) comparing to OVA group (Figure 3(b), P < 0.01). Results presented here suggest that GSI can effectively block Notch signaling.

Bottom Line: Th17 cell differentiation requires Notch signaling. γ-Secretase inhibitor (GSI) blocks Notch signaling; thus, it may be considered as a potential treatment for allergic asthma.GSI ameliorated the development of OVA-induced asthma, including suppressing airway inflammation responses and reducing the severity of clinical signs.GSI also significantly suppressed Th17-cell responses in spleen and reduced IL-17 levels in serum.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Pulmonology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou, Zhejiang 325027, China.

ABSTRACT
T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. Th17 cell differentiation requires Notch signaling. γ-Secretase inhibitor (GSI) blocks Notch signaling; thus, it may be considered as a potential treatment for allergic asthma. The aim of this study was to evaluate the effect of GSI on Th17 cell differentiation in a mouse model of allergic asthma. OVA was used to induce mouse asthma model in the presence and absence of GSI. GSI ameliorated the development of OVA-induced asthma, including suppressing airway inflammation responses and reducing the severity of clinical signs. GSI also significantly suppressed Th17-cell responses in spleen and reduced IL-17 levels in serum. These findings suggest that GSI directly regulates Th17 responses through a Notch signaling-dependent pathway in mouse model of allergic asthma, supporting the notion that GSI is a potential therapeutic agent for the treatment of allergic asthma.

No MeSH data available.


Related in: MedlinePlus