The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Goetzl, E. J.
Right arrow Articles by Voice, J. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Goetzl, E. J.
Right arrow Articles by Voice, J. K.
Right arrowPubmed/NCBI databases
*OMIM
*Compound via MeSH
*Substance via MeSH
The Journal of Immunology, 2000, 164: 4996-4999.
Copyright © 2000 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Differential Constitutive Expression of Functional Receptors for Lysophosphatidic Acid by Human Blood Lymphocytes1

Edward J. Goetzl2, Yvonne Kong and Julia K. Voice

Departments of Medicine and Microbiology-Immunology, University of California, San Francisco, CA 94143


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) from platelets and macrophages mediate T cell functions. Endothelial differentiation gene-encoded G protein-coupled receptors (Edg Rs) are specific for S1P (Edg-1, -3, -5, and -8 Rs) and LPA (Edg-2, -4, and -7 Rs). Human T cell tumors express many Edg Rs for both LPA and S1P. In contrast, human blood CD4+ T cells express predominantly Edg-4, and CD8+ T cells show only traces of Edg-2 and -5, by quantification of mRNA and Edg R Ags. LPA at 10-10–10-6 M suppressed significantly the secretion of IL-2 from anti-CD3 plus anti-CD28 Ab-challenged CD4+ T cells, but not CD8+ T cells. Monoclonal anti-Edg-4 R Ab, like LPA, suppressed stimulated IL-2 secretion from CD4+ T cells, but not CD8+ T cells. Constitutive expression of Edg-4 by CD4+, but not CD8+, human T cells accounts for differential functional responsiveness of the T cell subsets to LPA.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The lysophospholipid growth factors lysophosphatidic acid (LPA)3 and sphingosine 1-phosphate (S1P) are generated and released predominantly by platelets, macrophages, epithelial cells, and some tumor cells. LPS and S1P are bound extensively by albumin and other plasma proteins, and attain concentrations as high as micromolar in serum and tissues (1, 2, 3, 4). LPA and S1P both evoke proliferation and diverse functional responses of many types of cells by binding to one or more members of a subfamily of G protein-coupled receptors encoded by endothelial differentiation genes (Edg Rs) (5, 6, 7, 8). Edg Rs differ in lysophospholipid ligand specificity and relative levels of expression by each type of cell. Of the Edg Rs for which ligands have been defined, Edg-1, -3, -5, and -8 bind S1P most avidly, whereas Edg-2, -4, and -7 vastly prefer LPA.

LPA and S1P both stimulate and inhibit proliferation, enhance survival, suppress apoptosis, and elicit migration of T cell lymphoma or lymphoblastoma cells (9, 10, 11, 12, 13). In the few analyses of Edg Rs in such T cell lines, there was broad expression of Edg-1, -2, -3, -4, and -5 with quantitative predominance of Edg-2, -3, and -4 (11, 12, 14). Systematic evaluation of Edg Rs in human native immune cells and of the effects of LPA and S1P on immune functions of the major sets of normal T cells have not been undertaken previously, in part because of the unavailability of Abs highly specific for each Edg R. The present analyses of Edg Rs in human normal immune cells use recently generated mouse mAbs to peptide substituents of Edg Rs for Western blots in parallel with quantification of mRNA.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Isolation of human blood immune cells

Mixed mononuclear leukocytes were recovered from heparinized venous blood of healthy volunteers by centrifugation at 400 x g for 25 min at room temperature on Ficoll-Paque (Pharmacia, Piscataway, NJ), washed twice, and resuspended at 1 x 106/ml in RPMI 1640 containing 100 µg/ml fatty acid-free BSA (Calbiochem, La Jolla, CA) (RPMI 1640-faf-BSA). Monocytes and B cells, respectively, were isolated directly with metallic microbeads bearing anti-CD14 and anti-CD19 Abs before two cycles of magnetic retention chromatography (Miltenyi Biotec, Auburn, CA). CD4+ and CD8+ subsets of T cells were isolated from nonadherent mononuclear leukocytes by sequential reaction with biotinylated mouse monoclonal anti-human CD4 and anti-human CD8 Abs (PharMingen, San Diego, CA), respectively, washing, binding of streptavidin metallic microbeads (Miltenyi Biotec), and two cycles of magnetic retention chromatography. The purity of each set of mononuclear leukocytes was >96%, as assessed by flow cytometry.

RT-PCR semiquantification of mRNA encoding Edg receptors

Total cellular RNA was extracted by the TRIzol method (Life Technologies, Grand Island, NY) from suspensions of CD4+, CD8+, CD19+, and CD14+ sets of human blood cells, as well as four lines of rat HTC4 hepatoma cells, that have very low endogenous expression of native Edg-Rs and stably overexpress recombinant human Edg-2, -3, -4, or -5 Rs (15, 16). RT-PCR was performed as described (11, 15). [{alpha}-32P]dCTP, 2 µCi, was added to some sets of reaction mixtures to allow radioactive quantification of mRNA encoding each Edg R relative to that of the constitutive standard G3PDH (17). The sequences of oligonucleotide primer pairs for G3PDH and human Edg-1 to -5 have been provided (11, 12). The primers for Edg-7 were: 5'-CCATAGCAACCTGACCAAAAAGAG (450–473) and 5'-TCCTTGTAGGAGTAGATGATGGGG (909–932) (18). Ethidium bromide-stained G3PDH and Edg R cDNA bands were cut from 2 g/100 ml agarose gels and solubilized in 0.5 ml sodium perchlorate solution at 55°C for 1 h before ß-scintillation counting (Elu-Quick, Schleicher and Schuell, Keene, NH). Relative quantities of cDNA encoding each Edg R were expressed in terms of the ratio of radioactivity to that in the corresponding G3PDH band (11, 15).

Western blot analyses of Edg Rs

Proteins were extracted from replicate suspensions of 3–5 x 106 human purified immune cells and HTC4 cell Edg-2, -3, -4, and -5 R stable transfectants and resolved by electrophoresis with a rainbow-prestained set of m.w. markers (New England Nuclear, Boston, MA or Amersham, Arlington Heights, IL) as described (12, 15). Blots were developed with 0.5–1 µg/ml mouse monoclonal anti-Edg-2, -3, -4, or -5 R Ab and then HRP-labeled goat anti-mouse IgG, before development with an ECL kit (Amersham) (11, 12). The amino-terminal peptide epitopes for Edg-2, -3, -4, and -5 Rs consisted of amino acids 6–25, 1–21, 9–27, and 1–23, respectively.

Stimulation and quantification of IL-2 secretion by CD4+ and CD8+ T cells

Replicate suspensions of 3–4 x 105 CD4+ and CD8+ T cells in 0.5 ml RPMI 1640-faf-BSA with 100 U/ml penicillin and 100 µg/ml streptomycin were added to 24-well polystyrene plates without and with precoating by 0.5 µg each of mouse monoclonal anti-CD3 and anti-CD28 for 2 h at 37°C and 16 h at 4°C (PharMingen). T cells were incubated for 24 h at 37°C in 5% CO2 in air after addition of 10-11–10-6 M LPA, S1P, control phospholipids (Biomol, Plymouth Meeting, PA), an optimally effective amount of mouse monoclonal anti-Edg-4 R peptide Ab capable of signaling through the amino terminus of Edg-4 specifically (19), or mouse isotype-matched monoclonal anti-Edg-3 R amino-terminal peptide Ab in RPMI 1640-faf-BSA. Plates then were centrifuged at 1200 x g for 10 min at 4°C, and 150 µl of supernatant were removed from each well. The concentration of IL-2 in each well was determined by ELISA (Endogen, Woburn, MA), which is highly specific for human IL-2 and has a coefficient of variation <10% and a sensitivity of 6 pg/ml. As concentrations of IL-2 attained by CD4+ and CD8+ T cells stimulated with anti-CD3 plus anti-CD28 varied among sets from healthy volunteers by up to 10-fold, each control positive value was set at 100%, and the decreases achieved by lipids or anti-Edg R Ab were expressed as lower percentages of the control level. The significance of each mean decrease relative to each mean positive control value was calculated by a paired t test comparing every absolute suppressed value with the absolute value of its respective positive control.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Edg Rs expressed by the functionally distinct sets of immune cells isolated immunomagnetically from blood of healthy volunteers were mapped first by RT-PCR, using pools of first-strand cDNAs from 20 subjects of different ages, sexes, and races (Fig. 1Go). The CD4+ T cells and B cells had mRNA encoding predominantly Edg-4. Levels of Edg-2 and -3 mRNA much lower than that encoding Edg-4 were detected in CD4+ T cells and B cells of some subjects, and traces of Edg-5 rarely were found in CD4+ T cells (Table IGo). In sharp contrast, isolated CD8+ T cells had no detectable mRNA encoding Edg-4 R and only occasionally trace levels of Edg-2 and Edg-5 (Table IGo). Monocytes had similarly high levels of mRNA for Edg-2 and -3 Rs, but none for Edg-4 or -5. None of the immune cells had Edg-1 or -7 (Table IGo). The same sets of immune cells isolated immunomagnetically from venous blood of three additional normal subjects showed patterns with considerable individual variation in the minor bands, but with universal prominence of Edg-4 in CD4+ T cells and absence of Edg-4 from CD8+ T cells (Table IGo).



View larger version (33K):
[in this window]
[in a new window]
  		FIGURE 1. Semiquantitative PCR analyses of cDNAs encoding Edg-2 Rs, Edg-3 Rs, Edg-4 Rs, and Edg-5 Rs in human immune cells. Immune cells were from venous blood of 20 healthy female and male volunteers of different races and ages 27–58 years: CD4, helper/inducer T cells; CD8, suppressor/cytotoxic T cells; CD14, monocytes (M); and CD19, B cells (B). The ratio of 32P radioactivity in each Edg R PCR cDNA to that in the G3PDH cDNA is shown below the corresponding lane.

 

View this table:
[in this window]
[in a new window]
  		Table I. Relative levels of mRNA encoding Edg Rs in human blood immune cells1

 
Western blot analyses of the principal Edg-2 to -5 Rs detected in T cells and B cells by RT-PCR confirmed the striking differences in expression for the CD4+ and CD8+ subsets of T cells (Fig. 2Go). CD4+ T cells showed predominantly Edg-4 protein and only very low levels of Edg-2, -3, or -5 proteins. In contrast, CD8+ T cells showed no Edg-4 protein and either only very low levels of Edg-2 and/or -5 proteins or no Edg proteins. B cells had the expected predominance of Edg-4 with occasional traces of Edg-3. These constitutive patterns of expression of Edg Rs detected in human blood T cells predicted functional responses of the CD4+ subset to LPA and possibly high concentrations of S1P, but no responses of the CD8+ subset to either LPA or S1P.



View larger version (29K):
[in this window]
[in a new window]
  		FIGURE 2. Western blot of Edg Rs extracted from immune cells. The immune cells were isolated from a single healthy volunteer whose CD4+ cells had detectable mRNA for Edg-2, -3, and -5, as well as Edg-4, and CD8+ cells had mRNA for Edg-2 and -5, but B cells had mRNA only for Edg-4 (Table IGo). Two micrograms of cellular proteins from HTC4 cell standard transfectants (HS) and 10 µg from T helper cells (CD4), T suppressor cells (CD8), and B cells (B) were electrophoresed, transferred, and labeled with the anti-Edg R Abs noted for each frame. The horizontal line at the margin of each frame depicts the position of a 45-kDa prestained marker. This pattern is representative of those from five donors.

 
LPA and S1P both have many stimulatory and inhibitory effects on diverse functions of cultured lines of human neoplastic T cells. In such T cell lines, LPA and S1P evoke very similar patterns of functional responses (9, 10, 11, 12, 13, 14). However, LPA and S1P had very different effects in human blood-derived sets of T cells. LPA, but not S1P, inhibited IL-2 secretion by human blood CD4+ T cells stimulated with anti-CD3 plus anti-CD28 Abs (Fig. 3Go). Suppression of IL-2 secretion by stimulated CD4+ T cells was significant and increased in extent from 10-10–10-6 M LPA, attained mean maximum inhibition of 55% at 10-6 M LPA after 24 h, and was not accompanied by effects of LPA on IL-2 secretion by unstimulated CD4+ T cells or stimulated or unstimulated CD8+ T cells. S1P inhibited significantly, but modestly, stimulated secretion of IL-2 by CD4+ T cells only at 10-6 M (Fig. 3Go). The control lysophospholipids phosphatidic acid and sphingosine had no effect on stimulated IL-2 secretion by CD4+ T cells. The prominent suppressive activity of LPA for stimulated secretion of IL-2 by CD4+ T cells presumably is mediated by Edg-4 Rs, whereas the marginal activity of S1P for the same T cells is dependent on the lesser expression of Edg-3 Rs (Figs. 1Go and 2Go). The capacity of 10-6 M S1P to enhance secretion of IL-2 by unstimulated CD8+ T cells and to inhibit IL-2 secretion by stimulated CD8+ T cells is not explained by Edg R mediation but may reflect an intracellular messenger role of S1P (20).



View larger version (38K):
[in this window]
[in a new window]
  		FIGURE 3. LPA inhibition of IL-2 generation by CD4+ T cells but not by CD8+ T cells. Each bar and bracket depicts the mean ± SD of the results of three separate studies of T cells from three healthy volunteers. The respective control values (100%) in the absence of phospholipids showed ranges of: CD4+ in medium alone, 28–46 pg/ml; CD4+ with anti-CD3 plus anti-CD28 Abs, 214-1086 pg/ml; CD8+ in medium alone, 19–22 pg/ml; and CD8+ with anti-CD3 plus anti-CD28 Abs, 116–224 pg/ml. Exposure of CD4+ and CD8+ sets of T cells to anti-CD3 plus anti-CD28 mAbs for 24 h, under the conditions used to generate IL-2, did not change the patterns of relative expression of Edg Rs. The range of maximal inhibition by 10-6 M LPA of IL-2 secretion by stimulated CD4+ T cells was 32–61%. The symbols denoting statistical significance calculated by the paired t test were: *, p < 0.025; and **, p < 0.01.

 
A monoclonal anti-Edg-4 Ab directed to the amino terminus of Edg-4 Rs elicits cellular signals similar to those evoked by LPA in other types of human cells (19). This anti-Edg-4 R Ab, but not an isotype-matched monoclonal anti-Edg-3 R Ab, suppressed IL-2 secretion by stimulated CD4+ T cells, but not unstimulated CD4+ T cells or unstimulated or stimulated CD8+ T cells after 24 h (Fig. 4Go). The pattern of anti-Edg-4 R Ab inhibition of IL-2 secretion by sets of human blood T cells was identical with that observed with LPA.



View larger version (41K):
[in this window]
[in a new window]
  		FIGURE 4. Mouse monoclonal anti-Edg-4 R Ab inhibition of IL-2 generation by CD4+ T cells but not by CD8+ T cells. Each bar and bracket depicts the mean ± SD of the results of three separate studies of T cells from three healthy volunteers. The respective control values (100%) in the absence of Abs showed ranges of: CD4+ in medium alone, 26–35 pg/ml; CD4+ with anti-CD3 plus anti-CD28 Abs, 331-3587 pg/ml; CD8+ in medium alone, 29–68 pg/ml; and CD8+ with anti-CD3 plus anti-CD28 Abs, 164–710 pg/ml. The range of maximal inhibition by 10 µg/ml anti-Edg-4 R Ab of IL-2 secretion by stimulated CD4+ T cells was 33–56%. The symbols denoting statistical significance calculated by the paired t test were: +, p < 0.05; and *, p < 0.025.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Most types of cells of adult humans and other mammals, which have been studied to date, express two or more different Edg Rs in nearly equivalent abundance (5, 6, 7, 8). For example, endothelial cells have high levels of Edg-1, -2, and -3 Rs, whereas epithelial cells from several sources have similarly prominent levels of Edg-2, -3, and -5 Rs. The first analyses of Edg Rs and responses to LPA and S1P in cultured lines of T cell lymphomas and lymphoblastomas provided profiles of a breadth equivalent to or greater than nonlymphoid cells with predominant expression of Edg-2, -3, and -4, and lower levels of Edg-1 and -5 (11, 12, 14). It thus was surprising to find that freshly isolated human blood CD4+ T cells constitutively expressed predominantly Edg-4 Rs and only very low levels of Edg-2, -3, and/or -5. In contrast, CD8+ T cells isolated from the same donors had no Edg-4 Rs and only marginally detectable Edg-2 and/or Edg-5 or no detectable Edg Rs (Figs. 1Go and 2Go and Table IGo).

Inhibition of stimulated generation of IL-2 by LPA was observed only with CD4+ T cells and not CD8+ T cells (Fig. 3Go). This inhibition of IL-2 secretion by LPA, as for LPA suppression of proliferation of some T cell clones (9), was not blocked by prior treatment with pertussis toxin under conditions known to prevent Gi-mediated LPA enhancement of proliferation of many types of cells (7). Pertussis toxin-resistant regulation of cellular proliferation and functions by LPA in some cultured lines is mediated by ß{gamma} dimers of G proteins capable of sequentially altering phosphatidylinositol 3-kinase and extracellular signal-regulated kinases by ras-dependent or -independent mechanisms (21). A second pathway capable of regulating extracellular signal-regulated kinases involves suppression of oncogene-encoded and constitutively activated {alpha}i2, without involvement of ras (22). These alternative mechanisms must be examined in detail in different types of T cells to determine whether they participate in LPA suppression of IL-2 generation. Even less is known of the mechanisms that couple anti-Edg R Ab binding to Edg Rs with signals relevant to IL-2 generation. The current demonstration that CD4+ T cell Edg-4 R binding of anti-Edg-4 R Ab, but not Edg-3 R binding of anti-Edg-3 R Ab, suppresses stimulated secretion of IL-2 simply confirms a role for the Edg-4 R as the principal transducer of the suppressive effect of LPA (Figs. 3Go and 4Go).

Although the present data suggest the possibility of a predominant role for Edg-4 Rs in LPA effects on many CD4+ T cell activities, additional studies are required to establish such actions and to delineate any functionally relevant changes in expression of Edg Rs elicited by T cell stimuli. The combination of anti-CD3 plus anti-CD28 Abs did not change the profile of Edg Rs on CD4+ T cells or CD8+ T cells. The present results suggest that LPA occupies and activates Edg-4 Rs of Th1 cells, which are a major source of IL-2. This critical point must be examined in Th1 and Th2 cell clones and other defined populations, using a range of functional assays. If the differential activity of LPA for CD4+ T cells, as contrasted with CD8+ T cells, transcends a single function or if qualitatively distinctive effects are observed in Th1 and Th2 subsets, then LPA may be considered a significant specific immunoregulatory mediator.


   Acknowledgments
 
We thank Bethann Easterly for expert completion of all illustrations.


   Footnotes
 
1 This work was supported by National Institutes of Health Grant HL-31809. Back

2 Address correspondence and reprint requests to Dr. Edward J. Goetzl, University of California, UB8B, Box 0711, 533 Parnassus at 4th San Francisco, CA 94143-0711. Back

3 Abbreviations used in this paper: LPA, lysophosphatidic acid; S1P, sphingosine 1-phosphate; Edg R, G protein-coupled receptor encoded by an endothelial differentiation gene; faf-BSA, fatty acid-free BSA. Back

Received for publication February 3, 2000. Accepted for publication March 14, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Spiegel, S., S. Milstein. 1995. Sphingolipid metabolites: members of a new class of lipid second messengers. J. Membr. Biol. 146:225.[Medline]
  2. Moolenaar, W. H., O. Kranenburg, F. R. Postma, G. Zondag. 1997. Lysophosphatidic acid: G protein signaling and cellular responses. Curr. Opin. Cell Biol. 9:168.[Medline]
  3. Goetzl, E. J., S. An. 1998. Diversity of cellular receptors and functions for the lysophospholipid growth factors lysophosphatidic acid and sphingosine 1-phosphate. FASEB J. 12:1589.[Abstract/Free Full Text]
  4. An, S., E. J. Goetzl, H. Lee. 1998. Signaling mechanisms and molecular characteristics of G protein-coupled receptors for lysophosphatidic acid and sphingosine 1-phosphate. J. Cell. Biochem. Suppl. 30/31:147.
  5. Hecht, J. H., J. A. Weiner, S. R. Post, J. Chun. 1996. Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J. Cell Biol. 135:1071.[Abstract/Free Full Text]
  6. Lee, M.- J., J. R. Van Brocklyn, S. Thangada, C. H. Liu, A. R. Hand, R. Menzeleev, S. Spiegel, T. Hla. 1998. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279:1552.[Abstract/Free Full Text]
  7. Lynch, K. R., D. S. Im. 1999. Life on the Edg. Trends Pharmacol. Sci. 20:473.[Medline]
  8. Goetzl, E. J., and K. R. Lynch, eds.2000. Lysophospholipid and eicosanoid mediators in physiology and diseases. Ann. NY Acad. Sci. In press.
  9. Tigyi, G., D. L. Dyer, R. Miledi. 1994. Lysophosphatidic acid possesses dual action in cell proliferation. Proc. Natl. Acad. Sci. USA 91:1908.[Abstract/Free Full Text]
  10. Cuvillier, O., D. S. Rosenthal, M. E. Smulson, S. Spiegel. 1998. Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymphocytes. J. Biol. Chem. 273:2910.[Abstract/Free Full Text]
  11. Goetzl, E. J., Y. Kong, B. Mei. 1999. Lysophosphatidic acid and sphingosine 1-phosphate protection of T cells from apoptosis in association with suppression of Bax. J. Immunol. 162:2049.[Abstract/Free Full Text]
  12. Goetzl, E. J., Y. Kong, J. S. Kenney. 1999. Lysophospholipid enhancement of human T cell sensitivity to diphtheria toxin by increased expression of heparin-binding epidermal growth factor. Proc. Assoc. Am. Physicians 111:259.[Medline]
  13. Stam, J. C., F. Michiels, R. A. van der Kammen, W. H. Moolenaar, J. G. Collard. 1998. Invasion of T lymphoma cells: cooperation between Rho family GTPases and lysophospholipid receptor signaling. EMBO J. 17:4066.[Medline]
  14. Goetzl, E. J., Y. Kong, and J. K. Voice. 2000. Lysophosphatidic acid and sphingosine 1-phosphate stimulation of Jurkat T cell transmigration of a model basement membrane. FASEB J. In press (Abstr.).
  15. An, S., T. Bleu, O. G. Hallmark, E. J. Goetzl. 1998. Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid. J. Biol. Chem. 273:7906.[Abstract/Free Full Text]
  16. An, S., T. Bleu, Y. Zheng, E. J. Goetzl. 1998. Recombinant human G protein-coupled lysophosphatidic acid receptors mediate intracellular calcium mobilization. Mol. Pharmacol. 54:881.[Abstract/Free Full Text]
  17. Goetzl, E. J., H. Dolezalova, Y. Kong, L. Zeng. 1999. Dual mechanisms for lysophospholipid induction of proliferation of human breast carcinoma cells. Cancer Res. 59:4732.[Abstract/Free Full Text]
  18. Bandoh, K., J. Aoki, H. Hosono, S. Kobayashi, T. Kobayashi, K. Murakami-Murofushi, M. Tsugimoto, H. Arai, K. Inoue. 1999. Molecular cloning and characterization of a novel G protein-coupled receptor, EDG-7, for lysophosphatidic acid. J. Biol. Chem. 274:27776.[Abstract/Free Full Text]
  19. Goetzl, E. J., H. Dolezalova, Y. Kong, Y.-L. Hu, R. B. Jaffe, K. R. Kalli, C. A. Conover. 1999. Distinctive expression and functions of the type 4 endothelial differentiation gene-encoded G protein-coupled receptor for lysophosphatidic acid in ovarian cancer. Cancer Res. 59:5370.[Abstract/Free Full Text]
  20. Olivera, A., T. Kohama, L. Edsall, V. Nava, O. Cuvillier, S. Poulton, S. Spiegel. 1999. Sphingosine kinase expression increases intracellular sphingosine 1-phosphate and promotes cell growth and survival. J. Cell Biol. 147:545.[Abstract/Free Full Text]
  21. Hedin, K. E., M. P. Bell, C. J. Huntoon, L. M. Karnitz, D. J. McKean. 1999. Gi proteins use a novel ß/{gamma}- and ras-independent pathway to activate extracellular signal-regulated kinase and mobilize AP-1 transcription factors in Jurkat T lymphocytes. J. Biol. Chem. 274:19992.[Abstract/Free Full Text]
  22. Gupta, S. K., C. Gallego, G. L. Johnson, L. E. Heasley. 1992. MAP kinase (p42) is constitutively activated in gip2 and src transformed rat 1a fibroblasts. J. Biol. Chem. 267:7987.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Stem CellsHome page
M. Dottori, J. Leung, A. M. Turnley, and A. Pebay
Lysophosphatidic Acid Inhibits Neuronal Differentiation of Neural Stem/Progenitor Cells Derived from Human Embryonic Stem Cells
Stem Cells, May 1, 2008; 26(5): 1146 - 1154.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
K. Kotarsky, A. Boketoft, J. Bristulf, N. E. Nilsson, A. Norberg, S. Hansson, C. Owman, R. Sillard, L. M. F. Leeb-Lundberg, and B. Olde
Lysophosphatidic Acid Binds to and Activates GPR92, a G Protein-Coupled Receptor Highly Expressed in Gastrointestinal Lymphocytes
J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 619 - 628.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. Rubenfeld, J. Guo, N. Sookrung, R. Chen, W. Chaicumpa, V. Casolaro, Y. Zhao, V. Natarajan, and S. Georas
Lysophosphatidic acid enhances interleukin-13 gene expression and promoter activity in T cells
Am J Physiol Lung Cell Mol Physiol, January 1, 2006; 290(1): L66 - L74.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
D. A. Lin and J. A. Boyce
IL-4 Regulates MEK Expression Required for Lysophosphatidic Acid-Mediated Chemokine Generation by Human Mast Cells
J. Immunol., October 15, 2005; 175(8): 5430 - 5438.
[Abstract] [Full Text] [PDF]

Home page
 Stem CellsHome page
A. Pebay, R. C.B. Wong, S. M. Pitson, E. J. Wolvetang, G. S.-L. Peh, A. Filipczyk, K. L.L. Koh, I. Tellis, L. T.V. Nguyen, and M. F. Pera
Essential Roles of Sphingosine-1-Phosphate and Platelet-Derived Growth Factor in the Maintenance of Human Embryonic Stem Cells
Stem Cells, October 1, 2005; 23(10): 1541 - 1548.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
S. Bagga, K. S. Price, D. A. Lin, D. S. Friend, K. F. Austen, and J. A. Boyce
Lysophosphatidic acid accelerates the development of human mast cells
Blood, December 15, 2004; 104(13): 4080 - 4087.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
E. J. Goetzl and M. H. Graler
Sphingosine 1-phosphate and its type 1 G protein-coupled receptor: trophic support and functional regulation of T Lymphocytes
J. Leukoc. Biol., July 1, 2004; 76(1): 30 - 35.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
T. Kimura, A. M. Boehmler, G. Seitz, S. Kuci, T. Wiesner, V. Brinkmann, L. Kanz, and R. Mohle
The sphingosine 1-phosphate receptor agonist FTY720 supports CXCR4-dependent migration and bone marrow homing of human CD34+ progenitor cells
Blood, June 15, 2004; 103(12): 4478 - 4486.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
F. Gobeil Jr., S. G. Bernier, A. Vazquez-Tello, S. Brault, M. H. Beauchamp, C. Quiniou, A. M. Marrache, D. Checchin, F. Sennlaub, X. Hou, et al.
Modulation of Pro-inflammatory Gene Expression by Nuclear Lysophosphatidic Acid Receptor Type-1
J. Biol. Chem., October 3, 2003; 278(40): 38875 - 38883.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. H. Graeler, Y. Kong, J. S. Karliner, and E. J. Goetzl
Protein Kinase C {epsilon} Dependence of the Recovery from Down-regulation of S1P1 G Protein-coupled Receptors of T Lymphocytes
J. Biol. Chem., July 18, 2003; 278(30): 27737 - 27741.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
Y. Jin, E. Knudsen, L. Wang, Y. Bryceson, B. Damaj, S. Gessani, and A. A. Maghazachi
Sphingosine 1-phosphate is a novel inhibitor of T-cell proliferation
Blood, June 15, 2003; 101(12): 4909 - 4915.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
W. Drobnik, G. Liebisch, F.-X. Audebert, D. Frohlich, T. Gluck, P. Vogel, G. Rothe, and G. Schmitz
Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients
J. Lipid Res., April 1, 2003; 44(4): 754 - 761.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
M. GRAELER and E. J. GOETZL
Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells
FASEB J, December 1, 2002; 16(14): 1874 - 1878.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
D.-A. Wang, H. Du, J. H. Jaggar, D. N. Brindley, G. J. Tigyi, and M. A. Watsky
Injury-elicited differential transcriptional regulation of phospholipid growth factor receptors in the cornea
Am J Physiol Cell Physiol, December 1, 2002; 283(6): C1646 - C1654.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Graeler, G. Shankar, and E. J. Goetzl
Cutting Edge: Suppression of T Cell Chemotaxis by Sphingosine 1-Phosphate
J. Immunol., October 15, 2002; 169(8): 4084 - 4087.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
K. Fischer, D. Chatterjee, J. Torrelles, P. J. Brennan, S. H. E. Kaufmann, and U. E. Schaible
Mycobacterial Lysocardiolipin Is Exported from Phagosomes upon Cleavage of Cardiolipin by a Macrophage-Derived Lysosomal Phospholipase A2
J. Immunol., August 15, 2001; 167(4): 2187 - 2192.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
Y. Zheng, Y. Kong, and E. J. Goetzl
Lysophosphatidic Acid Receptor-Selective Effects on Jurkat T Cell Migration Through a Matrigel Model Basement Membrane
J. Immunol., February 15, 2001; 166(4): 2317 - 2322.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Goetzl, E. J.
Right arrow Articles by Voice, J. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Goetzl, E. J.
Right arrow Articles by Voice, J. K.
Right arrowPubmed/NCBI databases
*OMIM
*Compound via MeSH
*Substance via MeSH

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS