Mechanisms of Histamine's Effect on Lymphokine Secretion

描述（由申请人提供）：th2偏倚的细胞因子产生模式是哮喘受试者CD4+ T淋巴细胞的特征。尽管许多不同的因素已被证明可以控制CD4+Th亚群分化，但这些因素调节Th1/Th2细胞生成的机制尚不清楚。然而，最近的研究表明，Th1和Th2细胞产生的细胞因子差异在细胞因子基因转录水平上受到调节。这项工作旨在确定免疫调节和促炎剂，组胺对细胞因子和与Th2淋巴细胞相关的转录因子的药理学作用。组胺是Th1和Th2细胞因子产生的调节因子，通过环AMP、蛋白激酶a、酪氨酸激酶和STAT-1发挥作用。组胺抑制Th1细胞因子（IL-2和ifn - γ），并增强Th2细胞因子（IL-5、IL-10、IL-13）的产生。

DESCRIPTION (provided by the applicant): A Th2-biased cytokine production pattern is characteristic of CD4+ T lymphocytes of asthmatic subjects. Although many different factors have been shown to control CD4+Th subset differentiation, the mechanisms by which these factors regulate Th1/Th2 cell generation is poorly understood. Recent studies, however, have demonstrated that differential cytokine production by Th1 and Th2 cells is regulated at the level of cytokine gene transcription. This work seeks to define the pharmacologic effects of an immune regulatory and proinflammatory agent, histamine on cytokines, and transcription factors associated with Th2 lymphocytes. Histamine, a regulator of Th1 and Th2 cytokine production exerts its effects via cyclic AMP, protein kinase A, tyrosine kinase and STAT-1. Histamine suppresses Th1 cytokines (IL-2 and IFN-gamma) and enhances the production of Th2 cytokines (IL-5, IL-10, IL-13). The proposed study is designed to delineate the pharmacologic effects of histamine on Th1 vs. Th2 cells. We will assess the pharmacologic effects of histamine on IL-l0 and IL-13 production and their mRNA expression. We will determine whether histamine modulates cytokine-induced JAK-STAT transcription factors in Th1 and TH2 cells. The cytokine receptors utilize JAK-STAT pathways, and we propose that histamine regulates these events. Understanding of these pharmacologic mechanisms will provide further insight into the pathogenesis of asthma and will provide the foundation for the development of new therapies to control allergic disease and asthma.