Jia-Jun Liao

Lysophospholipid regulation of mononuclear phagocytes

Blood monocytes and tissue macrophages derived from monocyte differentiation in tissues are central elements of innate immunity in host defense against numerous pathogens and other challenges. These mononuclear phagocytes also participate in wound healing and normal tissue remodeling in development and growth. Pathological perversion of their physiological roles leads to participation of mononuclear phagocytes in fibrosing diseases including granulomatous disorders, chronic inflammation typical of arthritis, and atherosclerosis. Lysophospholipids, including lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are platelet-derived lipid growth factors considered to participate in leukocyte differentiation and activation. This section summarizes our recent observations of the effects of lysophospholipids on mononuclear phagocytes.

Distinctive T Cell-suppressive Signals from Nuclearized Type 1 Sphingosine 1-Phosphate G Protein-coupled Receptors

Sphingosine 1-phosphate (S1P) generated by cells of innate immunity and the type 1 S1P G protein-coupled receptor (S1P1) on mobile T cells constitute a major system for control of lymphoid organ traffic and tissue migration of T cells. Now we show that T cell activation mediated by the T cell antigen receptor translocates plasma membrane S1P1 to nuclear envelope membranes for association there with Gi/o, Erk ½, and other proteins that plasma membrane S1P1 uses to signal T cell proliferation. However, nuclear S1P1 and plasma membrane S1P1 transduce opposite effects of S1P on T cell proliferation and relevant signaling as exemplified by respective decreases and increases in T cell nuclear concentrations of both phospho-Erk and active (phosphorylated) c-Jun. T cell antigen receptor-mediated activation of T cells therefore both eliminates migration responses to S1P by down-regulation of plasma membrane S1P1 and translocates the S1P-S1P1 axis into the nuclear domain where signals are directed to transcriptional control of immune functions other than migration.

Lysophosphatidic Acid Inhibits Serum Deprivation-Induced Autophagy in Human Prostate Cancer PC-3 Cells

Lysophosphatidic acid (LPA) is a platelet-enriched bioactive lysophospholipid. By binding to its cognitive G protein-coupled receptors, which are encoded by endothelial differentiation genes (Edg), LPA regulates various cellular activities including proliferation, survival, and migration. Currently, little is known about the influences of LPA on autophagy, a pivotal mechanism for cell survival during conditions of starvation. Herein we present data indicating that LPA attenuates starvation-induced autophagy, by monitoring the percentage of LC3-II, an autophagy indicator, in human prostate PC-3 cells. In addition, by using cells stably expressing EGFP-LC3, LPA is shown to inhibit the formation of autophagosomes in serum-starved conditions. Our results suggest that in these conditions, LPA inhibits autophagy, which might facilitate early cancer development. Addendum to: Lysophosphatidic Acid (LPA) Inhibits Serum Starvation Induced-Autophagy of PC-3 Human Prostate Cancer Cell-Line,br>W.-P. Huang, J.-J. Liao and H. Lee FASEB J 2006; 20:12

Immunosuppressive human anti-lymphocyte autoantibodies specific for the type 1 sphingosine 1-phosphate receptor

Anti‐lymphocyte antibodies (Abs) that suppress T‐cell chemotactic and other responses to sphingosine 1‐phosphate (S1P), but not to chemokines, were found in a lymphopenic patient with recurrent infections. Lymphocyte type 1 S1P receptor (S1P1) that transduces S1P chemotactic stimulation was recognized by patient Abs in Western blots of T cells, S1P1 transfectants, and S1P1‐hemagglutinin purified by monoclonal anti‐hemagglutinin Ab absorption. The amino terminus of S1P1, but not any extracellular loop, preventedanti‐S1P1 Ab suppression of S1P1 signaling and T‐cell chemotaxis to S1P. Human purifiedanti‐S1P1 Abs decreased mouse blood lymphocyte levels by a mean of 72%, suppressed mouse T‐cell chemotaxis to S1P in vivo, and significantly reduced the severity of dextran sodium sulfate‐induced colitis in mice. Human Abs to the amino terminus of S1P1 suppress T‐cell trafficking sufficiently to impair host defense and provide therapeutic immunosuppression.—Liao, J.‐J., Huang, M.‐C., Fast, K., Gundling, K., Yadav, M., Van Brocklyn, J.R., Wabl, M.R., Goetzl, E.J. Immunosuppressive human anti‐lymphocyte autoantibodies specific for the type 1 sphingosine 1‐phosphate receptor. FASEB J. 23, 1786–1796 (2009)

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Prostate CancerPC-3 Cell Line

Lysophosphatidic acid (LPA) and Sphingosine 1-phosphate (S1P) are potent growth factors with diverse biological activities. There are many observations suggest that lysophospholipids are important on the regulation of cancer cell proliferation. LPA activates ERK pathway and induce proliferation of human prostate cancer cell line PC-3. However, the effect of S1P on prostate cancer is still poorly understood. In this study, we found that S1P caused cell cycle arrest in G1 phase and inhibit cell proliferation. S1P also induced morphological changes of cells and actin reorganization within 30 mins. In addition, S1P regulated the Edg receptors expression profile of PC-3 cells by itself. In conclusion, S1P might change the cell-ECM interaction through cytoskeleton reorganization and therefore influence cell proliferation in a time-dependent manner.