Function of prostaglandins and histamine in proliferation and differentiation of mast cells.

我们建立了原代肥大细胞培养体系，通过检测组胺脱羧酶（HDC）、PG合成酶和PG受体的表达来检测组胺和PG的功能。我们发现抗原-IgE复合物的刺激增加了考克斯-2、EP受体、IP和DP受体的表达。此外，我们阐明了HDC的细胞内定位和后跨国修饰之间的关系;这种酶是高度调节的蛋白酶体降解系统。从这些研究中，我们发现组胺和PG的产生以及PG受体的诱导是高度调节的，依赖于肥大细胞的分化。这些结果也表明，组胺和PGs可能参与肥大细胞的分化特异性过程，基于上述结果，我们研究了PGs和组胺在各种系统中的生理作用，包括肥大细胞功能，通过使用PG受体缺陷小鼠和HDC缺陷小鼠。我们建立 关于我们 艾德对每种类型前列腺素受体缺陷的小鼠进行了基因敲除，并通过检查每种基因敲除小鼠的表型阐明了前列腺素的生理作用：FP缺陷小鼠由于卵巢中持续产生孕酮而无法分娩幼崽，表明PGF 2 α在正常分娩所需的黄体溶解中发挥作用。IP缺陷小鼠表现出血栓形成倾向增加，炎症反应减少，并且没有表现出乙酸诱导的扭体反应，表明PGI 2参与促进炎症和疼痛感觉。EP 3缺陷小鼠对内源性和外源性热原均未显示发热反应; PGE 2通过EP 3介导热原诱导的发热产生。EP 4缺陷小鼠在出生后三天内由于动脉导管的通畅而死亡。PGE 2在通过EP 4关闭新生儿动脉导管中发挥着至关重要的作用。EP 2缺陷的雌性小鼠表现出由于排卵和受精受损而导致的生育力降低; PGE 2通过EP 2刺激卵丘扩张以及由此产生的cAMP水平增加而促进排卵和受精。通过这些研究，我们证明了受体亚型特异性活性的重要性。HDC缺陷型小鼠在IgE依赖性I型变态反应中表现出降低的反应，表明组胺在这种疾病中是必需的。少

We established primary culture system of bone marrow-derived mast cells, and examined function of histamine and PGs by monitoring expression of histidine decarboxylase(HDC), PG synthetases, and PG receptors. We found that stimulation of antigen-lgE complexes increase expression of COX-2, EP receptors, IP and DP receptors. In addition, we clarified relationship between intracellular localization of HDC and post-transnational modification; this enzyme is highly-regulated by the proteasome degradation system. From these studies, we found that production of histamine and PGs, and induction of PG receptors are highly-regulated dependent on differentiation of mast cells. These results also suggested that histamine and PGs may take part in differentiation-specific processes of mast cells.Based on findings described above, we examined physiological roles of PGs and histamine in various systems including mast cell function by using PG receptor-deficient mice and HDC-deficient mice. We establish … More ed mice deficient in each type of prostanoid receptors, and clarified physiological roles of prostanoids by examining phenotypes in each knockout mice : FP-deficient mice fail to deliver their pups due to persistent production of progesterone in ovaries, indicating that PGF2α plays a role in luteolysis required for normal parturition. IP-deficient mice showed increased tendency of thrombosis, reduced responses of inflammation, and did not show acetic acid-induced writhing responses, indicating that PGI2 participates in promotion of inflammation and pain sensation. EP3-deficent mice did not show febrile responses to both endogenous and exogenous pyrogen; PGE2 mediates pyrogen-induced fever generation via EP3. EP4-deficient mice died within three days after birth due to patency of ductus arteriosus. PGE2 plays an essential role in neonatal closure of ductus arteriosus via EP4. EP2-deficent female mice showed reduced fertility due to impaired ovulation and fertilization; PGE2 contributes to ovulation and fertilization through stimulation of cumulus expansion via EP2 and the resultant increase in cAMP level. Through these studies, we demonstrated importance of receptor subtype-specific activities. HDC-deficient mice showed reduced responses in lgE-dependent type l allergy, indicating that histamine is essential in this disease. Less