MONOCYTE CONTROL OF IL 4 EXPRESSION IN ATOPIC DERMATITIS

特应性皮炎(AD)的病理生理特点是 炎症超敏反应，免疫反应改变和 药理异常。这种情况有遗传基础， 基本的缺陷是由造血细胞携带的，通过 血液循环渗入皮肤和呼吸道组织。部分或全部 这些细胞具有异常活跃的环磷酸二酯酶(PDE)。 异构体。虽然AD的病因尚不完全清楚，但增加的 出生时脐带血单个核细胞中存在PDE活性， 在任何疾病的临床证据出现之前。我们最近的研究表明 证明了一种特征性的高活性IV型PDE亚型 在血液单核细胞中的存在与自发PGE2的增加有关 和IL-10的分泌，这些内源性调节介质抑制 辅助性T细胞1型(Th1)产生干扰素-γ。 最近的初步研究表明，单核细胞介质PGE2和PGE2 IL-10不仅抑制Th1，而且直接刺激Th2和特应性 T细胞反应更灵敏。特定的IV型PDE抑制剂可降低PGE2， 阿尔茨海默病患者外周血单个核细胞产生IL-10和IL-4的研究 恢复到正常水平。我们假设在特应性疾病中存在PDE异常 T细胞和单核细胞，导致IL-4表达增加 对单核细胞因子的反应。 我们预测在特应性皮炎中： 1)单核细胞因子IL-10和PGE2引起Th1/Th2平衡改变 对于Th2，考虑到AD的特征，如增加IgE产生， 细胞免疫和炎性高反应性降低，并且： 2)单核细胞PGE_2和IL-10产生增加， T细胞对IL-4的应答是由于环磷酸腺苷的PDE水解酶异常引起的。 拟议的研究将集中在单核细胞PGE2和IL-10的影响上 对T细胞和特应性T细胞反应的特性： 1)比较IL-10和PGE_2对特应症和正常对照的影响 外周血T细胞： A)对细胞因子产生的影响，特别是IL-4 和干扰素-γ； B)对激活反应性LL-4基因的评估 凝胶移位分析DNA结合蛋白； C)评估培养细胞的mRNA转录反应 细胞。 2)研究PDE异常与IL-4表达的关系： 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.