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PI3K and Notch signal pathways coordinately regulate the activation and proliferation of T lymphocytes in asthma
Weixi Zhang1, Ying Nie, Lei Chong
1Department of Pediatric Pulmonology, The Second Affiliated Hospital &Yuying Children's Hospital, Wenzhou Medical College, Wenzhou 325027, China.
Aims:
In the present study, we determined whether Phosphoinositide 3-kinase (PI3K) and Notch signal pathways are involved in the expression of cyclinD1, cyclinA and p27kip1 which were key molecules in controlling cell cycling from CD4(+) T lymphocyte in animal model of asthma.
Main Methods:
Ovalbumin (OVA) sensitized murine model of asthma was used to investigate the expression of cyclin D1, cyclin A, and p27kip1 by splenic CD4(+) T lymphocytes. We further observed the effect of specific inhibitor of PI3K(LY294002) and specific inhibitor of Notch(DAPT) on the proliferation of such CD4(+) T lymphocytes.
Key Findings:
We found that the expression of cyclinD1 and cyclinA was upregulated at both protein and mRNA levels in asthma group while p27kip1 was down-regulated. Both LY294002 and DAPT inhibit the proliferation of CD4(+) T lymphocytes in a time- and dose-dependent manner. Furthermore, LY294002 and DAPT have additive effect in down-regulation of cyclinD1 and upregulation of p27kip1. An upregulation of cyclinA, although not statistically significant, was also observed.
Significance:
These data suggested that PI3K signal pathway and Notch signal pathway may coordinately regulate the cell proliferation and differentiation processes through up-regulating cyclinD1 and down-regulating p27kip1 of CD4(+) T lymphocytes.
Insights
Phosphoinositide 3-kinase (PI3K) and Notch signaling pathways regulate CD4(+) T lymphocyte cell cycling in asthma. These pathways control cyclinD1, cyclinA, and p27kip1 expression, impacting T cell proliferation.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Asthma is characterized by airway inflammation involving T lymphocytes.
- Cell cycle regulators like cyclins and p27kip1 are crucial for T cell proliferation.
- The roles of PI3K and Notch signaling in asthma-related T cell dysregulation require further elucidation.
Purpose of the Study:
- To investigate the involvement of PI3K and Notch signaling pathways in regulating cell cycle molecules (cyclinD1, cyclinA, p27kip1) in CD4(+) T lymphocytes from a murine asthma model.
- To assess the impact of PI3K and Notch pathway inhibition on CD4(+) T lymphocyte proliferation.
Main Methods:
- An ovalbumin (OVA)-induced murine model of asthma was utilized.
- Expression of cyclin D1, cyclin A, and p27kip1 in splenic CD4(+) T lymphocytes was analyzed.
- Specific inhibitors of PI3K (LY294002) and Notch (DAPT) were used to evaluate their effects on T cell proliferation.
Main Results:
- Asthma model CD4(+) T lymphocytes showed increased cyclinD1 and cyclinA expression (mRNA and protein) and decreased p27kip1.
- Both PI3K inhibitor (LY294002) and Notch inhibitor (DAPT) suppressed CD4(+) T lymphocyte proliferation in a time- and dose-dependent manner.
- Combined inhibition by LY294002 and DAPT demonstrated additive effects in down-regulating cyclinD1 and up-regulating p27kip1.
Conclusions:
- PI3K and Notch signaling pathways coordinately regulate CD4(+) T lymphocyte proliferation and differentiation in asthma.
- These pathways exert their effects by modulating the expression of cyclinD1 and p27kip1.
- Targeting PI3K and Notch signaling represents a potential therapeutic strategy for asthma.
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