: 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.
