An investigation of the anti-inflammatory effects and a potential biomarker of PI3K inhibition in COPD T cells

作者：Khan Abid; Southworth Thomas; Worsley Sally; Sriskantharajah Srividya; Amour Augustin; Hessel Edith M; Singh Dave^*

来源：CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 2017, 44(9): 932-940.

DOI：10.1111/1440-1681.12784

• chronic obstructive pulmonary disease
• lymphocyte
• Phosphatidylinositol 3-kinase delta
• ribosomal protein S6

Lymphocyte numbers are increased in the lungs of chronic obstructive pulmonary disease (COPD) patients. Phosphatidylinositol-3-kinase delta (PI3K) is involved in lymphocyte activation. We investigated the effect of PI3K inhibition on cytokine release from COPD lymphocytes. We also evaluated phosphorylated ribosomal S6 protein (rS6) as a potential biomarker of PI3K activation. Peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage (BAL) cells isolated from healthy never smokers (HNS), smokers (S) and COPD patients were stimulated to induce a T cell receptor response. The effects of a PI3K specific inhibitor (GSK045) on cytokine release and rS6 phosphorylation were measured by Luminex and flow cytometry respectively. The effects of GSK045 on cytokine production from PHA stimulated chopped lung samples were investigated. GSK045 reduced cytokine release from PBMCs, BAL cells and chopped lung. Inhibition was greatest in the chopped lung model, with approximately 80% inhibition of interferon (IFN) , interleukin (IL)-2, IL-17 and IL-10. PI3K inhibition suppressed rS6 phosphorylation in unstimulated airway T-lymphocytes by up to 60%. Inhibition of PI3K suppressed T cell cytokine production in COPD patients. rS6 phosphorylation shows potential as a biomarker to assess PI3K activity.

• 出版日期2017-9