Potential role of phospholipase D2 in increasing interleukin-2 production by T-lymphocytes through activation of mitogen-activated protein kinases ERK1/ERK2

Biochim Biophys Acta. 2008 May;1781(5):263-9. doi: 10.1016/j.bbalip.2008.03.005. Epub 2008 Apr 1.

Abstract

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.

MeSH terms

  • Animals
  • Enzyme Activation
  • Humans
  • Interleukin-2 / immunology*
  • Ionomycin / metabolism
  • Ionophores / metabolism
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Jurkat Cells
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phospholipase D / genetics
  • Phospholipase D / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / immunology*
  • Tetradecanoylphorbol Acetate / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Interleukin-2
  • Ionophores
  • Isoenzymes
  • Ionomycin
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • phospholipase D2
  • Phospholipase D
  • ras Proteins
  • Tetradecanoylphorbol Acetate