The purpose of this proposal is to determine the role of leukotrienes and other lipoxygenase metabolites of arachidonc acid in human T cell activation and proliferation. Most of the work involves defining precisely what arachidonic acid metabolites are produced by T cells. I and my coworkers recently discovered that exogenous arachidonic acid substantially and in some cases totally inhibits leukotriene B4 (LTB4) production by mitogenstimulated T cells. Since all previously published studies on arachidonic acid metabolism of T cells included the addition of exogenous arachidonic acid to the culture media, this calls into question in generally accepted concept that T cells do not metabolize arachidonic acid in a major way. Our preliminary results show that LTB4 is the major arachidonic acid metabolize of T cells. In this study, I will attempt to characterize all arachidonic acid metabolities of human T cells and T cell lines using high performance liquid chromatography (HPLC) and radioimmunoassays (RIAs). T cells will be stimulated by a variety of compounds including mitogens, antigens, calcium ionophores, interleukin 1 (IL-1) and IL-2. The role of moncyte derived factors in T cell production of LTB4 will also be assessed. I will also continue my preliminary studies on the precise role of endogenous LTB4 in T cell proliferation. Preliminary results described in the proposal strongly suggest that endogenous LTB4 production is a necessary component of T cell proliferation in response to mitogens. LTB4 is necessary for phytohemagglutinin (PHA) induced IL-2 production, but it may also have a role in the response of activated T cells to IL-2. Future studies will examine the precise relationship between LTB4 production, IL-2 production and T cell proliferation in response to different stimuli, including so-called IL-2 independent mitogens. Both human peripheral blood T cells and a variety of human and murine T cell lines will be used in these experiments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA046964-06
Application #
3458782
Study Section
Biochemistry Study Section (BIO)
Project Start
1987-06-01
Project End
1993-06-30
Budget Start
1991-07-01
Budget End
1993-06-30
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Minneapolis Medical Research Fdn, Inc.
Department
Type
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55415
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Atluru, D; Gudapaty, S; O'Donnell, M P et al. (1993) Inhibition of human mononuclear cell proliferation, interleukin synthesis, mRNA for IL-2, IL-6, and leukotriene B4 synthesis by a lipoxygenase inhibitor. J Leukoc Biol 54:269-74
Olsen, S C; Atluru, D; Atluru, S et al. (1992) Inhibition of equine mononuclear cell proliferation and leukotriene B4 synthesis by a specific 5-lipoxygenase inhibitor, A-63162. Am J Vet Res 53:1015-8
Atluru, D; Gudapaty, S; Xue, W et al. (1992) In vitro inhibition of 5-lipoxygenase metabolite, leukotriene B4, in bovine mononuclear cells by bovine viral diarrhea virus. Vet Immunol Immunopathol 31:49-59
Atluru, D; Jackson, T M; Atluru, S (1991) Genistein, a selective protein tyrosine kinase inhibitor, inhibits interleukin-2 and leukotriene B4 production from human mononuclear cells. Clin Immunol Immunopathol 59:379-87
Atluru, D; Polam, S; Atluru, S et al. (1990) Regulation of mitogen-stimulated human T-cell proliferation, interleukin-2 production, and interleukin-2 receptor expression by protein kinase C inhibitor, H-7. Cell Immunol 129:310-20
Trevillyan, J M; Lu, Y L; Atluru, D et al. (1990) Differential inhibition of T cell receptor signal transduction and early activation events by a selective inhibitor of protein-tyrosine kinase. J Immunol 145:3223-30
Atluru, D; Xue, W; Polam, S et al. (1990) In vitro interactions of cytokines and bovine viral diarrhea virus in phytohemagglutinin-stimulated bovine mononuclear cells. Vet Immunol Immunopathol 25:47-59
Atluru, D; Polam, S; Sarraju, L et al. (1990) Inhibition of phytohemagglutinin-stimulated bovine mononuclear cell proliferation, interleukin-2 production and protein kinase C activity by a protein kinase C inhibitor, H-7. Vet Immunol Immunopathol 25:73-82