The Pathophysiological Roles of PI3Ks and Therapeutic Potential of Selective Inhibitors in Allergic Inflammation

Abstract

Phosphoinositide 3-kinases (PI3Ks) are known to be involved in a variety of cellular responses such as cell survival, proliferation, differentiation and cell migration. Recently, PI3Ks have been associated with the pathogenesis of asthma because various immune cells regulate allergic responses. Among the three classes of PI3Ks, the roles of PI3Kγ and PI3Kδ in allergic responses have attracted particular attention. In a previous report, allergic airway hyperresponsiveness (AHR), inflammation and airway remodeling in an ovalbumin-induced asthma model were decreased in PI3Kγ-deficient mice compared with wild-type mice. In addition, AHR and inflammation were attenuated by administration of a selective PI3Kδ inhibitor in a murine model of asthma. These results indicate that PI3Kγ and PI3Kδ may be new therapeutic targets for asthma. However, PI3Kγ and PI3Kδ may differ in terms of the mechanism of regulation. In this review, we focus on the roles of PI3Kγ and PI3Kδ in the pathogenesis of asthma and discuss the mechanistic differences between PI3Kγ and PI3Kδ.

T-helper cell type 2 (Th2) memory T cell-potentiating cytokine IL-25 has the potential to promote angiogenesis in asthma

“…The effects of IL-25 on angiogenesis were investigated using an in vitro angiogenesis assay (34,35) based on coculture of HUVEC for 11 d over a monolayer of irradiated fibroblasts (AngioKit; TCS CellWorks). Further details are given in SI Methods.…”

Phosphatidylinositol 3-Kinase Isoforms as Novel Drug Targets

“…The pathogennesis of asthma strongly depends on elevated levels of IgE antibodies and activation of immune cells such as T helper type 2 (T h 2) cells, mast cells, neutrophils, B cells and eosinophils, which produce a number of cytokines, chemokines, adhesion molecules, growth factors and enzymes contributing to disease progression (reviewed in [194]). PI3Ks are part of the complex signaling network involved in asthma development (reviewed in [195,196]). Genetic inactivation of p110δ in ovalbumin (OVA)-challenged mice decreased T h 2 cytokine-dependent airway inflammation, mucus production and reduced eosinophil recruitment [197].…”

Phosphatidylinositol 3-kinases pathway mediates lung caspase-1 activation and high mobility group box 1 production in a toluene-diisocyanate induced murine asthma model

“…PI3Ks are thought to be involved in a number of pathological states such as cancer, inflammation and allergy. Studies also showed that PI3K pathway plays a crucial role in the pathogenesis of asthma (Kampe et al, 2012;Ro et al, 2013;Takeda et al, 2010). In vitro, PI3K was required for activation of caspase-1, secretion of IL-1b and IL-18, as well as nucleocytoplasmic translocation of HMGB1 (Oh et al, 2009;Tapia-Abellan et al, 2014).…”