Leukotriene B4 (LTB4) is a distinct isomer of 5,12-dihydroxyeicosate- traenoic acid, which is generated by the 5-lipoxygenation of arachidonic acid in immunologically-activated mast cells, leukocytes, and some other types of cells. LTB4 is a potent mediator of diverse functions of polymorphonuclear (PMN) leukocytes and lymphocytes, as well as of endothelial, smooth muscle, and epithelial cells. The time-course of appearance and concentration of LTB4 in some human inflammatory lesions have suggested a pathogenetic role in cutaneous allergies, asthma, gout, spondyloarthritides, and rheumatoid arthritis. Responsive cells recognize LTB4 stereospecifically through one or more sets of plasma membrane receptors, which associate with Gi proteins. The results of the research proposed will increase our understanding of the genetic determinants, protein structure, and cellular properties of human leukocyte receptors for LTB4. The recent cloning and sequencing of a cDNA encoding the LTB4 receptor protein of human PMN leukocytes now will permit studies of the genetic control of receptor production and functions. The genomic organization and 5'-regulatory regions of the LTB4 receptor gene will be delineated and the pathways for processing newly-generated LTB4 receptor protein will be defined in cell-free model systems. The receptor protein structures required for cellular expression, as assessed by immunological and functional criteria, and for LTB4-binding specificity will be evaluated with mammalian cell transfectants bearing wild-type and various mutant receptors, in parallel with native leukocyte receptors. Selected biochemical and cellular characteristics of signal transduction by LTB4 receptors will be elucidated, including association with guanine nucleotide binding Gi proteins. effects on [Ca++]i and polyphosphoinositide- metabolism, regulation of membrane potential and ion transport, and LTB4- induced desensitization of LTB4 receptors. The distribution of LTB4 receptors on immune cells and in tissues responsive to LTB4 will be determined with both oligonucleotide probes and anti-receptor antibodies, in several models of cutaneous and pulmonary hypersensitivity. The resultant knowledge of LTB4 receptors on leukocytes and other cells will elucidate some mechanisms of immune induction of inflammation and other elements of hypersensitivity and may provide useful new tools for diagnosis and treatment of immunodeficiencies, allergic diseases, and autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL031809-09
Application #
3343015
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1983-07-01
Project End
1995-06-30
Budget Start
1991-07-05
Budget End
1992-06-30
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
Goetzl, Edward J; Huang, Mei-Chuan; Kon, Junko et al. (2010) Gender specificity of altered human immune cytokine profiles in aging. FASEB J 24:3580-9
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

Showing the most recent 10 out of 104 publications