Role of lysophosphatidylcholine in T-lymphocyte activation: involvement of phospholipase A2 in signal transduction through protein kinase C.

Abstract

ABSTRACT2-Lysophosphatidylcholine (lysoPtdCho), a product of the hydrolysis of phosphatidylcholine catalyzed by phospholipase A2, greatly potentiates the activation of human resting T lymphocytes that is induced by a membranepermeant diacylglycerol plus a calcium ionophore, as determined by the expression of the a subunit of the interleukin 2 receptor and thymidine incorporation into DNA. LysoPtdCho per se is inactive unless both diacylglycerol and a calcium ionophore are present. This effect of lysoPtdCho is also observed when diacylglycerol is replaced by a tumor-promoting phorbol ester. Other lysophosphatides including lysophosphatidylserine, lysophosphatidylinositol, and lysophosphatidic acid are inert except for lysophosphatidylethanolamine, which is far less effective than IysoPtdCho. Tracer experiments with radioactive choline indicate that, when T lymphocytes are stimulated with an antigenic signal, lysoPtdCho is indeed produced in a time-dependent fashion, although the concentration of this lysophospholipid accumulated remains to be quantitated. It suggests that phospholipase A2 is directly involved in the signal transduction pathway through protein kinase C to induce long-term cellular responses.A single dose of a tumor-promoting phorbol ester, together with a calcium ionophore, can induce T-lymphocyte activation, as determined by secretion of interleukin 2, expression of the a subunit of the interleukin 2 receptor (IL-2Ra), and incorporation of thymidine into DNA (for a review, see ref.1). On the other hand, a single dose of a membrane-permeant diacylglycerol (DAG) is normally insufficient to induce cell activation due to its rapid metabolism within the cell, and it is known that sustained activation of protein kinase C (PKC) by a large dose or repeated doses of a membrane-permeant DAG is essential to induce activation of T lymphocytes (2, 3). The formation of DAG from receptor-mediated hydrolysis of inositol phospholipids is, however, normally transient, and recent evidence strongly suggests that, at relatively later phases in cellular responses, DAG is produced from signalinduced breakdown of phosphatidylcholine (PtdCho), which is initiated presumably by the activation of phospholipase D (for reviews, see refs. 4 and 5). Previous reports from this laboratory (6, 7) suggest that cis-unsaturated fatty acids greatly enhance PKC activation when DAG is available. It has also been briefly described that 2-lysophosphatidylcholine (lysoPtdCho), the other product of receptor-mediated hydrolysis of PtdCho by phospholipase A2, synergizes with a membrane-permeant DAG to activate human resting T lymphocytes (8). In fact, activation of both phospholipase C and phospholipase A2 by a single agonist has been reported by Axelrod and coworkers (9). The receptor-mediated degradation of various membrane phospholipids, therefore, may be important in causing cellular responses such as cell proliferation and differentiation. The studies presented herein were undertaken to explore further the detailed kinects of the lysoPtd...

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