Anti-inflammatory potential of PI3Kδ and JAK inhibitors in asthma patients

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.

Phosphoinositide 3-kinase δ (PI3Kδ) in respiratory disease

“…PI3K is highly expressed within these cell types, and recent work demonstrates that Tcell derived cytokine generation can be suppressed by PI3K inhibition, with multiple T cell lineages targeted (17). Similar observations have also been demonstrated specifically in the context of COPD and asthma, with PI3K inhibition broadly reducing lymphocyte-derived cytokines such as IL-17 ( Figure 2A) (18,19). IL-17 is elevated within the airways of COPD patients and severe asthmatics, coordinating neutrophilic inflammation in these diseases (20,21).…”

“…expression is inducible under certain inflammatory conditions, for example in TNF-stimulated endothelial cells(25). Increased PI3K expression was observed in asthmatic versus healthy volunteer airway epithelial sample in human bronchial biopsies, although the expression was predominantly nuclear rather than cytoplasmic(18); the significance of this nuclear localisation is unclear. Might airway epithelial PIγK play a role in regulating airway inflammation in response to infection?…”

Non-eosinophilic asthma: current perspectives

“…Moreover, the combination of dexamethasone with either a JAK or PI3Kδ inhibitor showed an additive anti-inflammatory effect. 104 …”

Spectrum of T‐lymphocyte activities regulating allergic lung inflammation

“…Other drugs (tofacitinib, pyridine 6) targeting the JAK family members have been reported to reduce lung allergic responses in vivo . BAL cells from asthmatics and healthy controls cultured in the presence of tofacitinib alone or in combination with the corticosteroid dexamethasone (DEX) decreased the production of IFNγ, IL‐13, and IL‐17 . Unlike R256, these pan‐JAK inhibitors also altered Treg, Th1, and Th17 responses.…”