Antiproliferative properties of sphingosine-1-phosphate in human hepatic myofibroblasts

被引:115
作者
Pébay, A
Toutant, M
Prémont, J
Calvo, CF
Venance, L
Cordier, J
Glowinski, J
Tencé, M
机构
[1] Coll France, INSERM, U114, Chaire Neuropharmacol, F-75231 Paris 05, France
[2] Inst Fer Moulin, INSERM, U536, F-75005 Paris, France
关键词
calcium; cyclic AMP; Edg receptors; extracellular signal-regulated kinase (Erk); mouse; phospholipase C; proliferation;
D O I
10.1046/j.0953-816x.2001.01585.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Sphingosine-1-phosphate (S1P) is a potent lysophospholipid mediator mostly released by activated platelets. It is involved in several functions in peripheral tissues. but its effects in the central nervous system are poorly documented. Therefore, we have examined the effects of S1P on the proliferation of striatal astrocytes from the mouse embryo. These cells have been found to express mRNAs for the S1P receptors, Edg-1 and Edg-3. S1P stimulated thymidine incorporation and induced activation of extracellular signal-regulated kinases (Erks). Both effects were prevented by U0126, an Erk kinase inhibitor. The S1P-evoked activation of Erk1 was totally blocked in astrocytes pretreated with a combination of either phorbol ester (24 h) and LY294002, or phorbol ester (24 h) and pertussis toxin (PTX). Each individual treatment only partially inhibited Erk1 activation. This suggests that several separate mechanisms mediate this process, one involving protein kinase C and another involving Gi/Go proteins and phosphatidylinositol 3-kinase. In contrast, the stimulatory effect of SIP on astrocyte proliferation was totally blocked by either PTX or LY294002, but not by a downregulation of protein kinase C. S1P dramatically inhibited the evoked production of cyclic AMP, a response that was impaired by PTX. Finally, S1P stimulated the production of inositol phosphates and increased intracellular calcium by mobilization from thapsigargin-sensitive stores. These latter effects were mainly insensitive to PTX. Probably, Gi/Go protein activation and phosphoinositide hydrolysis are early events that regulate the activation of Erks by S1P. Altogether, these observations show that astrocytes are targets for S1P. Their proliferation in response to S1P could have physiopathological consequences at sites of brain lesions and alterations of the blood-brain barrier.
引用
收藏
页码:2067 / 2076
页数:10
相关论文
共 59 条
  • [11] SYNERGISTIC REGULATION OF CYTOSOLIC CA2+ CONCENTRATION BY ADENOSINE AND ALPHA-1-ADRENERGIC AGONISTS IN MOUSE STRIATAL ASTROCYTES
    DELUMEAU, JC
    TENCE, M
    MARIN, P
    CORDIER, J
    GLOWINSKI, J
    PREMONT, J
    [J]. EUROPEAN JOURNAL OF NEUROSCIENCE, 1991, 3 (06) : 539 - 550
  • [12] Derkinderen P, 1999, NEUROREPORT, V10, pR24
  • [13] Edsall LC, 1997, J NEUROSCI, V17, P6952
  • [14] Enzymatic measurement of sphingosine 1-phosphate
    Edsall, LC
    Spiegel, S
    [J]. ANALYTICAL BIOCHEMISTRY, 1999, 272 (01) : 80 - 86
  • [15] ELETR M, 1989, J NEUROSCI, V9, P1473
  • [16] Molecular cloning, tissue-specific expression, and chromosomal localization of a novel nerve growth factor-regulated G-protein-coupled receptor, nrg-1
    Glickman, M
    Malek, RL
    Kwitek-Black, AE
    Jacob, HJ
    Lee, NH
    [J]. MOLECULAR AND CELLULAR NEUROSCIENCE, 1999, 14 (02) : 141 - 152
  • [17] Diversity of cellular receptors and functions for the lysophospholipid growth factors lysophosphatidic acid and sphingosine 1-phosphate
    Goetzl, EJ
    An, SZ
    [J]. FASEB JOURNAL, 1998, 12 (15) : 1589 - 1598
  • [18] EDG6, a novel G-protein-coupled receptor related to receptors for bioactive lysophospholipids, is specifically expressed in lymphoid tissue
    Gräler, MH
    Bernhardt, G
    Lipp, M
    [J]. GENOMICS, 1998, 53 (02) : 164 - 169
  • [19] The pathways connecting G protein-coupled receptors to the nucleus through divergent mitogen-activated protein kinase cascades
    Gutkind, JS
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (04) : 1839 - 1842
  • [20] Phosphatidylinositol 3-kinase is an early intermediate in the G beta gamma-mediated mitogen-activated protein kinase signaling pathway
    Hawes, BE
    Luttrell, LM
    vanBiesen, T
    Lefkowitz, RJ
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (21) : 12133 - 12136