Abstract
Allergy is a major health problem, and this is especially true for type I allergy, such as bronchial asthma and allergic rhinoconjunctivitis, with more than 20% of the world population being affected by these conditions. Affected individuals exhibit a high titer of immunoglobulin E (IgE) antibodies specific for allergens such as those associated with house dust mites and plant pollen. Exposure of such individuals to these allergens induces the activation of mast cells through antigen-antibody-mediated cross-linking of IgE receptors on the cell surface. Activated mast cells release allergic mediators, such as histamine, cysteinyl leukotrienes, and various cytokines. These substances not only mediate acute allergic responses but also induce the late phase of inflammation by stimulating local synthesis of various chemokines such as CCL11 (eotaxin) and CCL17 (TARC) and recruiting T helper 2 (Th2) lymphocytes and eosinophils. Repeated exposure to allergens enhances inflammation characterized by infiltration of these cells and can cause tissue remodeling. However, how this course of responses is regulated and why it becomes exaggerated in some population to develop diseases remains unknown. Prostaglandins (PGs) including PGD2 and PGE2 are produced during allergic reactions. We have shown PGD2, which was released from activated mast cell, plays a role as a causative substance in allergic inflammation of airway. The concentrations of Th2 cytokines and the extent of lymphocyte accumulation in the lung of ovalbumin challenged PGD2 receptor (DP) deficient mice were greatly reduced compared with those in wild-type animals. Moreover, DP deficient mice showed only marginal infiltration of eosinophils and failed to develop airway hyperreactivity. Whereas PGD2 functions as an allergic mediator, aspirin-like drugs are generally ineffective in allergic disorders, suggesting that another PG-mediated pathway prevents the development of allergic reactions. Recently, we have shown that PGE2 acting at the EP3 receptor plays such a role. Mice lacking EP3 developed allergic inflammation markedly more pronounced than that in wild-type mice or mice deficient in other EP subtypes. Conversely, an EP3-selective agonist suppressed the inflammation. This suppression was effective when the compound was administered 3 h after antigen challenge and was associated with inhibition of antigen-induced changes in gene expression. Thus, PGD2 functions as a mast cell-derived mediator to trigger asthmatic responses. In contrast, the PGE2-EP3 pathway negatively modulates these reactions.
