Am J Physiol Cell Physiol Journal of Applied Physiology
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Am J Physiol Cell Physiol 274: C1573-C1582, 1998;
0363-6143/98 $5.00
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Vol. 274, Issue 6, C1573-C1582, June 1998

Growth factor-like action of lysophosphatidic acid on human B lymphoblasts

Dieter Rosskopf1, Wim Daelman1, Stefan Busch1, Markus Schürks1, Kathrin Hartung1, Andreas Kribben2, Martin C. Michel2, and Winfried Siffert1

1 Institut für Pharmakologie and 2 Abteilung für Nieren- und Hochdruckkrankheiten, Universitätsklinikum, D-45122 Essen, Germany

Proliferation and immunoglobulin secretion of B lymphocytes are regulated by specific antigens and numerous accessory immunomodulatory factors. Lysophosphatidic acid (LPA) is a glycerophospholipid mediator that is released from activated blood platelets, attains high levels in serum, and exerts potent stimulatory effects on, e.g., neutrophils, monocytes, and T lymphocytes. LPA is also generated by a secretory, cytokine-inducible phospholipase A2 present in high concentrations in inflammatory exudates and septic states. We investigated effects of LPA on human Epstein-Barr virus-immortalized B lymphoblasts, a model for immunoglobulin-secreting B cells. Intracellular Ca2+ was determined with fura 2 and the formation of inositol 1,4,5-trisphosphate by anion-exchange chromatography. LPA stimulated an increase in inositol 1,4,5-trisphosphate levels and induced a transient rise in intracellular free Ca2+ concentration from 105 ± 17 to 226 ± 21 nM. This Ca2+ signal resulted from Ca2+ mobilization and Ca2+ influx and was subject to homologous desensitization. Pertussis toxin inhibited these responses by ~70%. Furthermore, LPA stimulated a 27.5% increase in guanosine 5'-O-(3-thiotriphosphate) binding to permeabilized B lymphoblasts, which suggests the direct activation of pertussis toxin-sensitive G proteins by LPA. LPA stimulated a strong increase in the specific phosphorylation of the mitogen-activated protein kinase (immunoblot analysis) that was prevented by the MEK inhibitor PD-98059. Finally, LPA triggered a 2-fold increase in DNA synthesis ([3H]thymidine incorporation) and a 2-fold increase in B lymphoblast number and evoked a 20- to 50-fold increase in immunoglobulin formation. By RT-PCR we detected specific mRNA transcripts for the recently cloned human LPA receptor. Thus our data suggest that LPA behaves as a B cell growth factor.

G protein-coupled receptor; signal transduction; pertussis toxin; immunoglobulin; proliferation; phospholipase A2


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