Abstract
BackgroundPhosphatidylinositol 3-kinase delta (PI3Kδ) and Janus-activated kinases (JAK) are both novel anti-inflammatory targets in asthma that affect lymphocyte activation. We have investigated the anti-inflammatory effects of PI3Kδ and JAK inhibition on cytokine release from asthma bronchoalveolar lavage (BAL) cells and T-cell activation, and measured lung PI3Kδ and JAK signalling pathway expression.MethodCells isolated from asthma patients and healthy subjects were treated with PI3Kδ or JAK inhibitors, and/or dexamethasone, before T-cell receptor stimulation. Levels of IFNγ, IL-13 and IL-17 were measured by ELISA and flow cytometry was used to assess T-cell activation. PI3Kδ, PI3Kγ, phosphorylated protein kinase B (pAKT) and Signal Transducer and Activator of Transcription (STAT) protein expression were assessed by immunohistochemistry in bronchial biopsy tissue from asthma patients and healthy subjects. PI3Kδ expression in BAL CD3 cells was measured by flow cytometry.ResultsJAK and PI3Kδ inhibitors reduced cytokine levels from both asthma and healthy BAL cells. Combining dexamethasone with either a JAK or PI3Kδ inhibitor showed an additive anti-inflammatory effect. JAK and PI3Kδ inhibitors were shown to have direct effects on T-cell activation. Immunohistochemistry showed increased numbers of PI3Kδ expressing cells in asthma bronchial tissue compared to controls. Asthma CD3 cells in BAL expressed higher levels of PI3Kδ protein compared to healthy cells.ConclusionsTargeting PI3Kδ or JAK may prove effective in reducing T-cell activation and the resulting cytokine production in asthma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0436-2) contains supplementary material, which is available to authorized users.
Highlights
Phosphatidylinositol 3-kinase delta (PI3Kδ) and Janus-activated kinases (JAK) are both novel anti-inflammatory targets in asthma that affect lymphocyte activation
Targeting PI3Kδ or JAK may prove effective in reducing T-cell activation and the resulting cytokine production in asthma
The aims of this study were to evaluate the anti-inflammatory effects of PI3Kδ and JAK inhibition on release of T-cell derived cytokines from asthma bronchoalveolar lavage (BAL) cells, and to investigate activation of these pathways in asthma patients compared to healthy subjects by immunohistochemical analysis of PI3Kδ, Phosphatidylinositol 3-kinase gamma (PI3Kγ), Phophorylated protein kinase B (pAKT) and pSTAT proteins in bronchial biopsies
Summary
Phosphatidylinositol 3-kinase delta (PI3Kδ) and Janus-activated kinases (JAK) are both novel anti-inflammatory targets in asthma that affect lymphocyte activation. Airway inflammation is a key feature of asthma. There are increased lymphocyte numbers in the lungs of patients with asthma, with many patients showing a T-helper 2 (TH2) response, associated with eosinophilic inflammation [1]. There is evidence of an increased T-helper 1 (TH1) response in asthma, with IFNγ overproduction [2], and a role for T-helper 17 (TH17) cells in promoting neutrophilic inflammation in asthma [3]. STATs act as transcription factors, and play a key role in lymphocyte differentiation and activation; IL-12 induces STAT4 activation promoting TH1 differentiation, IL-4 activates STAT6 promoting TH2 differentiation and IL-6, IL-21 and IL-23 all stimulate STAT3-dependent TH17 differentiation [6, 7]
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