Tomomi Tanigai

Allergic airway hyperresponsiveness, inflammation, and remodeling do not develop in phosphoinositide 3-kinase γ–deficient mice

BACKGROUND Bronchial asthma is characterized by chronic airway inflammation caused by inflammatory cells. Phosphoinositide 3-kinases (PI3Ks) are known to play a prominent role in fundamental cellular responses of various inflammatory cells, including proliferation, differentiation, and cell migration. PI3Ks therefore are expected to have therapeutic potential for asthma. Although some investigations of the involvement between the pathogenesis of asthma and PI3K have been performed, it is unknown whether PI3Kgamma, a PI3K isoform, is involved in the pathogenesis of asthma. OBJECTIVE We investigated the role of PI3Kgamma in allergen-induced allergic airway inflammation, airway hyperresponsiveness (AHR), and airway remodeling with PI3Kgamma-deficient mice. METHODS After ovalbumin (OVA) sensitization, wild-type (WT) and PI3Kgamma-deficient mice were exposed to aerosolized OVA 3 days per week for 5 weeks. RESULTS In OVA-sensitized and OVA-challenged (OVA/OVA) PI3Kgamma-deficient mice, levels of airway inflammation, AHR, and airway remodeling were significantly decreased compared with those in OVA/OVA WT mice. On the other hand, no significant differences were detected in serum OVA-specific IgE and IgG1 levels and CD4/CD8 balance in bronchoalveolar lavage fluid between OVA/OVA WT mice and OVA/OVA PI3Kgamma-deficient mice. To determine in which phase of allergic responses PI3Kgamma plays a role, we transferred splenocytes from OVA-sensitized WT or PI3Kgamma-deficient mice to naive mice of either genotype. Similar increased levels of eosinophils were induced in both WT recipient mice but not in both PI3Kgamma-deficient recipient mice. CONCLUSION PI3Kgamma might be involved in allergic airway inflammation, AHR, and airway remodeling by regulating the challenge/effector phase of allergic responses.

The pathophysiological roles of PI3Ks and therapeutic potential of selective inhibitors in allergic inflammation.

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.

Possible novel receptor for PGD2 on human bronchial epithelial cells.

Prostaglandin D2 (PGD2), a major prostanoid produced by activated mast cells, has long been implicated in allergic diseases. Recent studies have shown that PGD2 exerts its effects through two different G-protein-coupled receptors (GPCRs), the D-prostanoid receptor (DP) and the chemoattractant receptor-homologous molecule expressed on T helper type-2 cells (CRTH2), expressed in various human tissues. The PGD2/CRTH2 system mediates the chemotaxis of eosinophils, basophils, and Th2 cells, which are involved in the induction of allergic inflammation. We have reported that normal human bronchial epithelial cells (NHBE) and epithelial cell lines (NCI-H292) expressed CRTH2, and PGD2 induces production of IL-8 and GM-CSF. This review discusses the role of CRTH2/DP on epithelial cells and mentions a possible novel receptor for PGD2.

Docosahexaenoic Acid Exerts Anti-Inflammatory Action on Human Eosinophils through Peroxisome Proliferator-Activated Receptor-Independent Mechanisms

Background: Despite the fact that previous studies have indicated the significant roles of polyunsaturated fatty acids (PUFAs) in the immune system through peroxisome proliferator-activated receptor alpha (PPARα) and PPARγ, the biological functions and the mechanisms of action in eosinophils are poorly understood. Methods: We investigated the functional effects of docosahexaenoic acid (DHA, n-3 PUFA) on human peripheral blood eosinophils, using in vitro systems to test the hypothesis that DHA negatively regulates eosinophil mechanisms through PPARα and PPARγ. Results: Eosinophil apoptosis that spontaneously occurs under normal culture conditions was accelerated in the presence of DHA. In addition, eotaxin-directed eosinophil chemotactic responses were inhibited by pretreatment with DHA, disturbing both the velocity and the directionality of the cell movement. Pharmacological manipulations with specific antagonists indicated that the effects of DHA were not mediated through PPARα and PPARγ, despite the presence of these nuclear receptors. DHA also induced Fas receptor expression and caspase-3 activation that appears to be associated with a proapoptotic effect of DHA. Further, DHA rapidly inhibited the expression of eotaxin receptor C-C chemokine receptor 3 and eotaxin-induced calcium influx and phosphorylation of extracellular signal-regulated kinase. Interestingly, these inhibitory effects were not observed with linoleic acid (n-6 PUFA). Conclusions: The data might explain one of the mechanisms found in previous research showing the favorable effects of n-3 PUFA supplementation on allergic diseases, and provide novel therapeutic strategies to treat eosinophilic disorders.

Regulation of Peroxisome Proliferator-Activated Receptor-γ Expression in Human Eosinophils by Estradiol

Background: Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor that regulates not only adipogenesis but also immune reaction. We previously demonstrated that human eosinophils expressed functional PPARγ, although the modulator of PPARγ expression is less well understood. Because clinical studies have shown that the efficacy of PPARγ agonists as insulin sensitizers is stronger in women than in men, we investigated whether sex hormones caused any changes in eosinophil PPARγ expression levels. Methods: First, purified human peripheral blood eosinophils were cultured with 17β-estradiol for 24 h, followed by PPARγ measurement using a flow cytometer. Next, eosinophil PPARγ expression and serum estradiol were studied in 10 healthy women during the menstrual and follicular phases to identify the physiological significance of estradiol. Eosinophil PPARγ expression was also compared in 22 men, 21 non-pregnant women, and 15 pregnant women. Results: We observed that PPARγ protein expression in eosinophils was significantly enhanced by 10–6M 17β-estradiol. Although serum estradiol concentration was increased during the follicular phase, PPARγ expression levels were not affected by the menstrual cycle. In addition, no significant differences in PPARγ expression were observed in terms of sex and pregnancy. Conclusions: These findings suggest that estradiol potentially upregulates eosinophil PPARγ expression in vitro, although some other mechanisms might be involved in its regulation in vivo.

Effect of the Hepatocyte Growth Factor on Allergic Inflammatory Cells

Hepatocyte growth factor (HGF) has multiple activities in a variety of tissues, and is known to prevent the onset and progression of various diseases, but the mechanisms by which HGF exert its beneficial effects remain to be elucidated, although many studies have shown that HGF exerts anti-inflammatory effects in multiple animal models of diseases of the liver, kidney, lung and other organs. Recently, we have reported that HGF also reduces allergic airway inflammation in a murine model of asthma by ovalbumin. Furthermore, HGF directly modulates various functions of eosinophils, which have been shown to play a pivotal role in the development of allergic airway inflammation. HGF influences a number of cell types, and regulates various biological activities, including cytokine production, cell migration, proliferation and survival. This review focuses on the effect of HGF on various inflammatory cells, e.g. eosinophils and dendritic cells, in allergic reactions.