Hikari Kato

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.

Retinoic acids are potent inhibitors of spontaneous human eosinophil apoptosis.

Retinoic acids (RAs), which are active metabolites of vitamin A, are known to enhance Th2-type immune responses in vitro, but the role of RAs in allergic inflammatory cells remains unclear. In this study, we demonstrated that purified peripheral blood eosinophils expressed nuclear receptors for RAs at the mRNA and protein levels. Eosinophils cultured with all-trans RA (ATRA) and 9-cis-RA showed dramatically induced cell survival and nuclear hypersegmentation, and the efficacy of RAs (10−6M) was similar to that of IL-5 (1 ng/ml), the most critical cytokine for eosinophil activation. Pharmacological manipulation with receptor-specific agonists and antagonists indicated that the antiapoptotic effect of RAs was mediated through ligand-dependent activation of both retinoid acid receptors and retinoid X receptors (mainly retinoid acid receptors). Furthermore, using a gene microarray and a cytokine Ab array, we discovered that RAs induced vascular endothelial growth factor, M-CSF, and MCP-1 secretion, although they were not involved in eosinophil survival. RA-induced eosinophil survival appears to be associated with down-regulation of caspase 3 and inhibition of its enzymatic activity. These findings indicate an important role of RAs in homeostasis of granulocytes and provide further insight into the cellular and molecular pathogenesis of allergic reactions.

Leptin has a priming effect on eotaxin-induced human eosinophil chemotaxis.

Background: Tissue eosinophilia is one of the hallmarks of allergic diseases and Th2-type immune responses including asthma. Systemic inflammation caused by adipose tissue in obesity via production of adipokines such as leptin has been attracting attention recently as a contributor to exacerbation of allergic immune reactions. In this study, we examined whether leptin might affect eosinophil chemotactic responses. Methods: Peripheral blood eosinophils were purified, and the effect of leptin on eosinophil migration was investigated using in vitro systems. Results: High concentrations of leptin induced eosinophil chemotaxis and rapid phosphorylation of ERK1/2 and p38 mitogen-activated protein kinase but not calcium mobilization. We also found that pretreatment of eosinophils with physiological concentrations of leptin amplified the chemotactic responses to eotaxin. This leptin-primed chemotaxis appears to be associated with increased calcium mobilization but not with ERK1/2 and p38 pathways. Conclusions: These results indicate that leptin has both direct and indirect effects on eosinophil chemotaxis and intracellular signaling. In physiological settings, leptin may maintain eosinophil accumulation at allergic inflammatory foci.

Obesity and Eosinophilic Inflammation: Does Leptin Play a Role

It has been pointed out that obesity is a risk factor for, and is involved in the exacerbation of asthma. Mounting evidence about adipose tissue-derived proteins (adipokines) gave rise to the current understanding of obesity as a systemic inflammatory disorder. In this review, we summarized the involvement of leptin, focusing on eosinophil functions. Several studies have indicated that leptin can restrain eosinophil apoptosis, enhance migration, increase adhesion molecules and induce cytokine production. Since leptin also acts on a variety of immune cells related to allergic response, increased leptin in obese individuals potentially explains the mechanism by which obesity leads to an exacerbation of asthma. Further studies targeting adipokines will delineate the association between obesity and eosinophil-associated diseases.

Soluble vascular cell adhesion molecule-1 induces human eosinophil migration

Background:  Tissue eosinophilia is one of the hallmarks of allergic diseases and Th2‐type immune responses including asthma. Adhesion molecules are known to play an important role in the accumulation of eosinophils in allergic inflammatory foci, and they contribute to eosinophil activation. Elevated levels of the soluble forms of adhesion molecules in the body fluid of asthmatic patients have been observed, although their pathophysiological significance remains to be fully elucidated.

Hepatocyte growth factor attenuates eotaxin and PGD2-induced chemotaxis of human eosinophils

Background:  Hepatocyte growth factor (HGF) is known to influence a number of cell types, and regulate various biologic activities including cell migration, proliferation, and survival. In a recent study, we found that, in vivo, HGF suppresses allergic airway inflammation, i.e. the infiltration of inflammatory cells including eosinophils into the airway, and further, that HGF reduces Th2 cytokine levels; however, the directly physiologic role of HGF with eosinophils remains unclear. In this study, we investigate the potential of recombinant HGF to regulate the factor‐induced chemotaxis of human eosinophils.

Theophylline and Dexamethasone Induce Peroxisome Proliferator-Activated Receptor-γ Expression in Human Eosinophils

Eosinophils are major effector cells in allergic diseases including asthma. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor that regulates immune reaction. We have previously demonstrated that human eosinophils express PPARγ and that stimulation with a synthetic agonist for PPARγ attenuated the factor-induced eosinophil survival and chemotaxis. However, the modulator of the eosinophil PPARγ expression has not yet been studied. In this study, we investigated the effect of theophylline and dexamethasone (widely used drugs in the treatment of asthma) on PPARγ expression in eosinophils. Purified human peripheral blood eosinophils were cultured, and therapeutic concentrations of theophylline and dexamethasone were added. Subsequently, PPARγ was measured using quantitative real-time RT-PCR and flow cytometry. Theophylline and dexamethasone markedly enhanced both mRNA and protein levels of PPARγ. These findings suggest that the increase in PPARγ expression on eosinophils may play a role in the anti-inflammatory effects of theophylline and dexamethasone.

Anti- and Proinflammatory Effects of 15-Deoxy-Δ12,14-Prostaglandin J2(15d-PGJ2) on Human Eosinophil Functions

The cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is recognized as a potent lipid mediator that is derived from PGD2, which is produced abundantly in allergic inflammatory sites. It is now established that 15d-PGJ2 negatively regulates cellular functions through its intracellular targets such as peroxisome proliferator-activated receptor-γ (PPARγ). However, recent studies revealed that 15d-PGJ2 appears to possess not only anti-inflammatory activities but also a proinflammatory potential depending on its concentration and the activation state of the target cell. For instance, at low concentrations, 15d-PGJ2 enhances eotaxin-induced chemotaxis, shape change, and actin reorganization in eosinophils through its ligation with PPARγ. Moreover, 15d-PGJ2 itself is a potent chemoattractant, and it induces calcium mobilization, and up-regulates CD11b expression through its membrane receptor – chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Conversely, at high concentrations, 15d-PGJ2 inhibits eosinophil survival by inducing apoptosis in a PPARγ-independent manner. Here, we discuss the pathophysiological roles of 15d-PGJ2 that could act as a paracrine, autocrine, and intracrine substance to regulate eosinophil functions.

Anti-Allergic Inflammatory Effects of Hepatocyte Growth Factor

Hepatocyte growth factor (HGF) is known to influence a number of cell types and regulate various biological activities including cytokine production, cell migration, proliferation and survival. Thus, HGF is now recognized to be a key factor in the prevention and attenuation of disease progression. We have reported that HGF reduces allergic airway inflammation, airway hyperresponsiveness, remodeling and development of Th2 cytokines as well as growth factors such as transforming growth factor-β in vivo. In vitro, HGF directly attenuates chemotaxis of eosinophils in the absence of Th2 cytokines and modulates mitogen-activated protein kinases, which play an important role in eosinophil migration. In this review, we discuss the physiological role of HGF in allergic inflammation and its mechanism of anti-inflammatory effects, including the regulation of eosinophil functions.

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.