PI3K and Notch signal pathways coordinately regulate the activation and proliferation of T lymphocytes in asthma

Life Sci. 2013 May 20;92(17-19):890-5. doi: 10.1016/j.lfs.2013.03.005. Epub 2013 Apr 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / metabolism*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Proliferation / drug effects
  • Chromones / administration & dosage
  • Chromones / pharmacology
  • Cyclin A / genetics
  • Cyclin D1 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Dipeptides / administration & dosage
  • Dipeptides / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Morpholines / administration & dosage
  • Morpholines / pharmacology
  • Ovalbumin
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Messenger / metabolism
  • Receptors, Notch / antagonists & inhibitors
  • Receptors, Notch / metabolism*
  • Signal Transduction / drug effects
  • Spleen / cytology
  • Spleen / metabolism
  • Time Factors
  • Up-Regulation / drug effects

Substances

  • Ccnd1 protein, mouse
  • Cdkn1b protein, mouse
  • Chromones
  • Cyclin A
  • Dipeptides
  • Morpholines
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Messenger
  • Receptors, Notch
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Ovalbumin