The purpose of this proposal is to determine the role of lipoxygenase metabolites of arachidonic acid in humoral and cellular immune function of human lymphocytes in vitro. We hypothesize that the actions of corticosteroids in various assays of immune function are due to inhibition of arachidonic acid metabolism. More specifically, because the actions of corticosteroids on in vitro assays of immune function are not shared by cyclooxygenase inhibitors, we propose that corticosteroids affect immune functions by preventing the synthesis of lipoxygenase metabolites. If so, lipoxygenase inhibitors should mimick the effect of corticosteroids, and exogenous arachidonic acid should reverse their effect. In addition, there should exist specific lipoxygenase metabolites, such as leukotrienes, that have the opposite effect of corticosteroids in a given in vitro immunologic system. Our preliminary data supports the above hypothesis. For example, corticosteroids inhibit suppressor cell induction and two lipoxygenase metabolites, leukotriene B4 (LTB4) and 15-hydroperoxyeicosatetranoic acid (154-HPETE) stimulate suppressor cell development. In addition LTB4 in low concentrations reverses the inhibition of mitogen induced blastogenesis by hydrocortisone. We propose to more extensively test the hypothesis that corticosteroids act by blocking the generation of lipoxygenase metabolites in a number of immunologic assays. This will at the same time allow us to characterize the role of specific lipoxygenase metabolites in those assays. We will continue to study the LTB4-induced suppressor cell, focusing on the apparent switch in phenotype from OKT8(-) to OKT8(+) in T cells cultured with LTB4. We wish to determine more precisely the phenotype of the precursor of the LTB4 suppressor cell, and whether other cells, such as suppressor inducer cells, are necessary for its generation. Additional experiments will examine the function of LTB4-induced suppressor cells in patients with systemic lupus erythematosus and other conditions with disordered suppressor cell function.
| Behrens, T W; Goodwin, J S (1990) Control of human T cell proliferation by platelet-activating factor. Int J Immunopharmacol 12:175-84 |
| Sierakowski, S; Kucharz, E J; Lightfoot, R W et al. (1989) Impaired T-cell activation in patients with systemic lupus erythematosus. J Clin Immunol 9:469-76 |
| Behrens, T W; Lum, L G; Lianos, E A et al. (1989) Lipoxygenase inhibitors enhance the proliferation of human B cells. J Immunol 143:2285-94 |
| Sierakowski, S; Goodwin, J S (1988) Mechanism of action of glucocorticoid-induced immunoglobulin production: II. Requirement for fetal calf serum. Clin Exp Immunol 71:198-201 |
