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Am J Physiol Lung Cell Mol Physiol 281: L108-L118, 2001;
1040-0605/01 $5.00
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Vol. 281, Issue 1, L108-L118, July 2001

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

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

Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900

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)-alpha 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-alpha using C2 ceramide as a cell-penetrating sphingolipid representative of the metabolites induced by TNF-alpha . We found that in H441 cells, as reported in other cell types, cytosolic phospholipase A2 (cPLA2) is activated by TNF-alpha . We also observed that the inhibiting action of C2 ceramide on CT requires protein kinase C-alpha , 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-alpha 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.

lung injury; pulmonary surfactant; phosphatidylcholine synthesis; leukotrienes; cytidine 5'-triphosphate; protein kinase C; mitogen-activated protein kinase; cytosolic phospholipase A2


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