CTP:Phosphocholine cytidylyltransferase inhibition by ceramide via PKC-α, p38 MAPK, cPLA2, and 5-lipoxygenase

Shanjana Awasthi, Jeevalatha Vivekananda, Vibhudutta Awasthi, Dolphin Smith, Richard J. King

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

In a companion paper (Vivekananda J, Smith D, and King RJ. Am J Physiol Lung Cell Mol Physiol 281: L98-L107, 2001), we demonstrated that tumor necrosis factor (TNF)-α inhibited the activity of CTP:phosphocholine cytidylyltransferase (CT), the rate-limiting enzyme in the de novo synthesis of phosphatidylcholine (PC), and that its actions were likely exerted through a metabolite of sphingomyelin. In this paper, we explore the signaling pathway employed by TNF-α using C2 ceramide as a cell-penetrating sphingolipid representative of the metabolites induced by TNF-α. We found that in H441 cells, as reported in other cell types, cytosolic phospholipase A2 (cPLA2) is activated by TNF-α. We also observed that the inhibiting action of C2 ceramide on CT requires protein kinase C-α, p38 mitogen-activated protein kinase, and cPLA2. The actions of C2 ceramide on CT activity can be duplicated by adding 2 μM lysoPC to these cells. Furthermore, we found that the effects of C2 ceramide are dependent on 5-lipoxygenase but that cyclooxygenase II is unimportant. We hypothesize that CT activity is inhibited by the lysoPC generated as a consequence of the activation of cPLA2 by protein kinase C-α and p38 mitogen-activated protein kinase. The other product of the activation of cPLA2, arachidonic acid, is a substrate for the synthesis of leukotrienes, which raise intracellular Ca2+ levels and complete the activation of cPLA2.

Original languageEnglish (US)
Pages (from-to)L108-L118
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume281
Issue number1 25-1
DOIs
StatePublished - 2001

Keywords

  • Cytidine 5′-triphosphate
  • Cytosolic phospholipase A
  • Leukotrienes
  • Lung injury
  • Mitogen-activated protein kinase
  • Phosphatidylcholine synthesis
  • Protein kinase C
  • Pulmonary surfactant

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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