MONOCYTE CONTROL OF IL 4 EXPRESSION IN ATOPIC DERMATITIS

特应性皮炎（AD）的病理生理学特征为： 炎性超敏反应，改变的免疫反应和 药理生理学异常这种情况有遗传基础， 基本缺陷由造血细胞携带， 血液循环渗透到皮肤和呼吸道组织。中的一些或全部 这些细胞具有异常活性的环腺苷酸磷酸二酯酶（PDE）， 同种型。虽然AD的病因尚不完全清楚，但AD的发病率增加。 出生时，PDE活性存在于脐带血单核细胞中， 在任何疾病的临床证据出现之前。我们最近的研究 证明了特征性高活性IV型PDE同种型 存在于血液单核细胞中与自发性PGE 2增加有关 和IL-10分泌，并且这些内源性调节介质抑制 1型T辅助细胞（Th 1）产生干扰素γ（IFN-γ）。 最近的初步研究表明，单核细胞介质PGE 2和 IL-10不仅抑制Th 1，而且直接刺激Th 2， T细胞反应更灵敏。特异性IV型PDE抑制剂减少PGE 2， AD外周血单核细胞（PBMC）中IL-10和IL-4的产生 到正常水平。我们假设PDE异常存在于特应性 T细胞以及单核细胞中IL-4的表达增加，导致IL-4的表达增加。 对单核细胞因子的反应。 我们预测，在特应性皮炎： 1)单核细胞因子IL-1 O和PGE 2引起Th 1/Th 2平衡的改变 向Th 2，解释了诸如IgE产生增加的AD特征， 细胞介导的免疫力降低和炎症高反应性，以及： 2)单核细胞PGE 2和IL-10的产生增加， T细胞IL-4应答由环AMP的异常PDE水解引起。 本研究将重点关注单核细胞PGE 2和IL-10对单核细胞增殖的影响。 对T细胞和特应性T细胞反应的特征： 1)比较IL-10和PGE_2对特应性和正常人的作用， 外周血T细胞： a）对细胞因子产生的影响，尤其是IL-4 和IFN-γ; B）活化应答性IL-4基因的评估 DNA结合蛋白凝胶迁移分析; c）评估培养的细胞中的mRNA转录应答， 细胞 2)为了研究异常PDE与IL-4表达之间的关系： a）选择性PDE抑制剂对IL-4的影响 生产; B）对IL-4启动子结合蛋白的抑制剂作用。

The pathophysiology of atopic dermatitis (AD) is characterized by inflammatory hypersensitivity, altered immunological responses and pharmacophysiological aberrancies. The condition has a genetic basis and the basic defect is carried by hematopoietic cells which travel through the circulation to infiltrate skin and respiratory tissues. Some or all of these cells have abnormally active cyclic AMP-phosphodiesterase (PDE) isoforms. Though the etiology of AD is not entirely clear, the increased PDE activity is present at birth in cord blood mononuclear cells, well before any clinical evidence of disease appears. Our recent studies have demonstrated that a characteristic high activity Type IV PDE isoform present in blood monocytes is associated with increased spontaneous PGE2 and lL-10 secretion and that these endogenous regulatory mediators inhibit production of interferon gamma (IFN-y) by T helper type 1 (Th1) cells. Recent preliminary studies indicate that the monocyte mediators PGE2 and lL-10 not only inhibit Th1, but directly stimulate Th2 and that the atopic T cells are more responsive. Specific Type IV PDE inhibitors reduce PGE2, IL-10 and IL-4 production in AD peripheral blood mononuclear cells (PBMC) to normal levels. We hypothesize that a PDE abnormality resides in atopic T cells, as well as in monocytes, causing increased lL-4 expression in response to the monocyte factors. We predict that in atopic dermatitis: 1) Monocyte factors IL-1O and PGE2 cause a shift in Th1/Th2 equilibrium toward Th2, accounting for such AD features as increased IgE production, decreased cell mediated immunity and inflammatory hyperreactivity, and: 2) both the increased monocyte PGE2 and IL-1O production and the increased T cell lL-4 responses result from abnormal PDE hydrolysis of cyclic AMP. The proposed study will focus upon the effects monocyte PGE2 and lL-1O have on T cells and the characteristics of atopic T cell responses: 1) To compare the effects of lL-1O and PGE2 on atopic and normal peripheral blood T cells: a) effects on cytokine production, especially IL-4 and IFN-y; b) assessment of activation responsive lL-4 gene DNA-binding proteins by gel shift assay; c) assessing mRNA transcriptional responses in cultured cells. 2) To study the relationship between abnormal PDE and lL-4 expression: a) the effect of selective PDE inhibitors on IL-4 production; b) inhibitor effects on lL-4 promotor-binding proteins.