Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are mediators of cellular proliferation and functions, which are produced by platelets, thymic epithelial cells, macrophages and other phagocytes. Endothelial differentiation genes encode a subfamily of G protein-coupled receptors (GPCRs), termed Edg Rs, of which Edg-l, -3, -5, and -8 Rs are specific for S1P and Edg-2, -4, and -7 Rs for LPA. Thymocytes and T cells express high levels of Edg Rs in distinctive patterns. The predominant Edg Rs expressed are: 3 and 5 for S1P by thymocytes, 4 by CD4+ T cells constitutively, 2 and 4 for LPA by activated CD4+ T cells, and only traces of 2 and 5, but not 4, by CD8+ T cells before and after activation. The central working hypothesis is that CD4+ cells recognize and respond to LPA differently in two specific states of Edg R expression: prior to activation Edg-4 Rs dominate and mediate adhesion and migration, but suppress proliferation and IL-2 generation, whereas after activation Edg-2 Rs dominate and mediate proliferation and cytokine generation, but inhibit migration.
The specific aims are: 1. Edg Rs will be delineated in mouse and human T cell subsets, B cells and macrophages using newly developed panels of mouse and rat monoclonal anti-Edg R antibodies. 2. Determinants of developmental and constitutive expression of Edg-4 Rs by CD4+ T cells will be defined and mechanisms of Edg-4 R signaling and effects elucidated in CD4+ T cells and Th1 and Th2 subsets. 3. Mechanisms of cytokine-mediated upregulation of Edg-2 Rs in CD4+ T cells will be delineated and pathways of Edg-2 R signaling and effects characterized in CD4+ T cells and Th1 and Th2 subsets. 4. Signaling and functional interactions among Edg-2, -3 and -4 Rs will be analyzed in Jurkat T cell transfectants. 5. Edg R transduction of T cell protection from apoptosis will be studied to characterize the distinctive mechanisms of LPA and SIP suppression of Bax and inhibition of caspases. A greater knowledge of Edg R expression and functions in T cells will reveal specific mechanisms of lysolipid phosphate immunoregulation and identify new targets for correcting immune disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL031809-18A1
Application #
6263095
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1983-07-01
Project End
2004-08-31
Budget Start
2000-09-30
Budget End
2001-08-31
Support Year
18
Fiscal Year
2000
Total Cost
$295,000
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Huang, Mei-Chuan; Patel, Kalpesh; Taub, Dennis D et al. (2010) Human CD4- 8- T cells are a distinctive immunoregulatory subset. FASEB J 24:2558-66
Yeh, Che-Chung; Li, Hongzhe; Malhotra, Deepak et al. (2009) Sphingolipid signaling and treatment during remodeling of the uninfarcted ventricular wall after myocardial infarction. Am J Physiol Heart Circ Physiol 296:H1193-9
Liao, Jia-Jun; Huang, Mei-Chuan; Fast, Katharine et al. (2009) Immunosuppressive human anti-lymphocyte autoantibodies specific for the type 1 sphingosine 1-phosphate receptor. FASEB J 23:1786-96
Goetzl, Edward J; Liao, Jia-Jun; Huang, Mei-Chuan (2008) Regulation of the roles of sphingosine 1-phosphate and its type 1 G protein-coupled receptor in T cell immunity and autoimmunity. Biochim Biophys Acta 1781:503-7
Huang, Mei-Chuan; Liao, Jia-Jun; Bonasera, Stephen et al. (2008) Nuclear factor-kappaB-dependent reversal of aging-induced alterations in T cell cytokines. FASEB J 22:2142-50
Liao, Jia-Jun; Huang, Mei-Chuan; Goetzl, Edward J (2007) Cutting edge: Alternative signaling of Th17 cell development by sphingosine 1-phosphate. J Immunol 178:5425-8
Goetzl, Edward J; Wang, Wengang; McGiffert, Christine et al. (2007) Sphingosine 1-phosphate as an intracellular messenger and extracellular mediator in immunity. Acta Paediatr Suppl 96:49-52
Wang, Wengang; Huang, Mei-Chuan; Goetzl, Edward J (2007) Type 1 sphingosine 1-phosphate G protein-coupled receptor (S1P1) mediation of enhanced IL-4 generation by CD4 T cells from S1P1 transgenic mice. J Immunol 178:4885-90
Huang, Mei-Chuan; Watson, Susan R; Liao, Jia-Jun et al. (2007) Th17 augmentation in OTII TCR plus T cell-selective type 1 sphingosine 1-phosphate receptor double transgenic mice. J Immunol 178:6806-13

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