Leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are products of specific cellular oxygenation of arachidonic acid, that potently mediate physiological responses, inflammatory reactions and distinctive functions of lymphocytes and other immune cells. The specificity of the effects of PGE2 and LTB4 are attributable to recognition by unique subsets of high- affinity receptors (Rs) or the G protein-associated superfamily, that differ in the diversity of structural isomers, signal transduction pathways, susceptibility to desensitization and tissue distribution. The first specific aim of this proposal is to delineate critical structural determinants of ligand binding, signal transduction and cellular desensitization for the principal isomers of the LTB4Rs and the EP2-subtype of PGE2Rs, that predominate in cortical thymocytes, mature lymphocytes and other leukocytes. Stable transfectants expressing the wild-type and selected mutant Rs, and cultured lines of human and mouse T cells bearing PGE2Rs and/or LTB4Rs will be used to examine structural determinants of these R functions. The second specific aim is to determine the characteristics and mechanisms of responses of the LTB4Rs and EP2Rs of transfectants, T cells and selected tissues to homologous ligand, cross-reacting stimuli, and selected immune cytokines. The distribution of EP2Rs and LTB4Rs in normal and diseased skin, lung and immune tissues will be delineated and changes will be defined in relation to evoked immune reactions in murine lung tissues. The third specific aim is to elucidate recently identified roles of LTB4 and PGE2 in mediating positive and negative selection of developing thymocytes, that express higher levels of the respective Rs than mature T cells. The mechanisms by which LTB4 and PGE2 stimulate both chemotaxis and chemokinesis of T cells and their surface expression of matrix metalloproteinases 2, 3 and 9, that are required for migration through connective tissues, will be established for the major subsets of T cells and cultured lines of defined phenotypes. The effects of genetic, immunochemical and pharmacologic alterations in R density and signaling on thymocyte selection and T cell migration will be examined to identify approaches of potential use in the treatment of T cell-predominant inflammatory and immune diseases.
Showing the most recent 10 out of 104 publications
