Potential role of phospholipase D2 in increasing interleukin-2 production by T-lymphocytes through activation of mitogen-activated protein kinases ERK1/ERK2.
Hydrolysis of phosphatidylcholine by phospholipase D (PLD) leads to the generation of phosphatidic acid (PA), which is itself a source of diacylglycerol (DAG). These two versatile lipid second messengers are at the centre of a phospholipid signalling network and as such are involved in several cellular functions. However, their role in T-cell activation and functions are still enigmatic. In order to elucidate this role, we generated a human and a murine T-cell line that stably overexpressed the PLD2 isoform. Analysis of the Ras-MAPK pathway upon phorbol myristate acetate (PMA) and ionomycin stimulation revealed that PLD2 promoted an early and sustained increase in ERK1/2 phosphorylation in both cell lines. This response was inhibited by 1-butanol, a well known distracter of PLD activity, or upon overexpression of a dominant negative PLD2, and it was concomitant with a boost of PA/DAG production. As a functional consequence of this PLD2-dependent MAPK activation, interleukin-2 production evoked by PMA/ionomycin stimulation or CD3/CD28 engagement was enhanced in the two T-cell lines overexpressing PLD2. Thus, PLD2 emerged as an early player upstream of the Ras-MAPK-IL-2 pathway in T-cells via PA and DAG production, raising new possibilities of pharmacological manipulation in immune disorders.
Hamdi
Safouane M
SM
INSERM U563, CHU Purpan, Toulouse, France. safouane.hamdi@toulouse.inserm.fr
Cariven
Clotilde
C
Coronas
Sophie
S
Malet
Nicole
N
Chap
Hugues
H
Perret
Bertrand
B
Salles
Jean-Pierre
JP
Record
Michel
M
D000818:Animals; D004789:Enzyme Activation; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology*; D015759:Ionomycin / Q000378:metabolism; D007476:Ionophores / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D007376:Interleukin-2; D007476:Ionophores; D007527:Isoenzymes; D015759:Ionomycin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C105606:phospholipase D2; D010739:Phospholipase D; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate