An investigation of the anti‐inflammatory effects and a potential biomarker of PI 3Kδ inhibition in COPD T cells

Lymphocyte numbers are increased in the lungs of chronic obstructive pulmonary disease ( COPD ) patients. Phosphatidylinositol‐3‐kinase delta ( PI 3Kδ) is involved in lymphocyte activation. We investigated the effect of PI 3Kδ inhibition on cytokine release from COPD lymphocytes. We also evaluated phosphorylated ribosomal S6 protein ( rS 6) as a potential biomarker of PI 3Kδ activation. Peripheral blood mononuclear cells ( PBMC s) 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 PI 3Kδ specific inhibitor ( GSK 045) on cytokine release and rS 6 phosphorylation were measured by Luminex and flow cytometry respectively. The effects of GSK 045 on cytokine production from PHA stimulated chopped lung samples were investigated. GSK 045 reduced cytokine release from PBMC s, BAL cells and chopped lung. Inhibition was greatest in the chopped lung model, with approximately 80% inhibition of interferon ( IFN ) γ, interleukin ( IL )‐2, IL ‐17 and IL ‐10. PI 3Kδ inhibition suppressed rS 6 phosphorylation in unstimulated airway T‐lymphocytes by up to 60%. Inhibition of PI 3Kδ suppressed T cell cytokine production in COPD patients. rS 6 phosphorylation shows potential as a biomarker to assess PI 3Kδ activity.