Novel function of prostaglandin D2 and its metabolites in pathogenesis of immune and allergic diseases as examined by prostaglandin D synthase gene-manipulated mice

点击翻译按钮获取中文摘要

To examine the effects of overproduction of prostaglandin (PG) D2 on the inflammatory and allergic reactions, we generated transgenic (TG) mice that over-expressed human PGD synthase under the control of the a-actin promotor. In an ovalbumin (OVA)-induced asthma model, eosinophils and lymphocytes infiltrated into the bronchoalveolar lavage (BAL) fluid of TG mice more significantly than that of the wild-type (WT) mice, at 1 and 3 days after OVA-challenge. The levels of IL-4, IL-5 and eotaxin in the BAL fluid were also significantly higher in TG mice than those in WT mice, although the IFNa level was decreased in TG mice as compared with WT mice. The increases in Th2 cytokines in the BAL fluid and the extent of lymphocyte accumulation in the lung after OVA-challenge were greatly reduced in PGD2 receptor gene-knockout (DP-/-) mice compared with those in WT mice. Moreover, DP-/- mice showed only marginal infiltration of eosinophils and failed to develop airway hyperreactivity. These results, taken together, indicate that PGD2 acts as a mediator to trigger asthmatic responses. PGD2 is also produced as a major prostanoid in the central nervous system and acts as a potent sleep-inducing substance. We therefore studied the sleep behavior of TG mice. Although no difference was observed in the sleep/awake patterns between WT and TG mice, a striking time-dependent increase in non-rapid eye movement (NREM) sleep was observed in TG mice after stimulation by tail clipping. Induction of NREM sleep in TG mice was positively correlated with the PGD2 production in the brain. Sleep and PGD2 content in the brain were essentially unchanged in WT mice after tail clipping. These results with TG mice demonstrate the involvement of PGD2, PGD synthase, and its gene in the regulation of NREM sleep.