Regulation of interleukin-2 responses by phosphatidic acid.
Interleukin-2 (IL-2) plays a central role in the immune system by regulating the proliferation and differentiation of T lymphocytes. However, the molecular mechanism of the signal transduction through the IL-2 receptor is poorly understood. We have studied the role of phosphatidic acid (PA) on IL-2 signal transduction using cloned T lymphocytes. IL-2 stimulated a transient increase in the PA concentration in resting CTLL-2 cells prelabeled with [3H]palmitic acid. This effect was detected as early as 1 min after IL-2 addition and peaked at 5 min. IL-2 similarly increased phospholipase D activity in intact CTLL-2 cells, as inferred by phosphatidylethanol production. By contrast, IL-2 did not affect [3H]palmitic acid-labeled diacylglycerol levels. Furthermore, exogenous addition of several natural or synthetic PA to T cells mimicked IL-2 activity. Thus, PA were able to induce DNA synthesis on CTLL-2 cells, although this effect was only 10%-20% of that observed with IL-2. PA showed a synergistic effect with low doses of IL-2. In addition, PA was able to induce c-myc RNA transcription in CTLL-2 cells as well as IL-2 receptor (CD25) expression on the cell membrane with equal potency as saturating doses of IL-2. It is likely that IL-2-induced PA accumulation is a consequence of phospholipase D activation. This hypothesis is further supported by the fact that the addition of exogenous phospholipase D but not phosphatidylinositol-specific phospholipase C also reproduced the IL-2 or PA effects mentioned above. In summary, our results suggest a role of phospholipase D activation and PA formation as second messengers of IL-2 activity.
Cano
E
E
Centro de Biología Molecular, UAM-CSIC Universidad Autónoma de Madrid Cantoblanco, Spain.
Muñoz-Fernández
M A
MA
Fresno
M
M
D000818:Animals; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc; D007376:Interleukin-2 / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010712:Phosphatidic Acids / Q000378:metabolism / Q000494:pharmacology*; D010739:Phospholipase D / Q000032:analysis / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D007376:Interleukin-2; D010712:Phosphatidic Acids; D015375:Receptors, Interleukin-2; D010739:Phospholipase D