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Phospholipase D1 Plays a Key Role in TNF- Signaling¹

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

The primary characteristic features of any inflammatory or infectious lesions are immune cell infiltration, cellular proliferation, and the generation of proinflammatory mediators. TNF- is a potent proinflammatory and immuno-regulatory cytokine. Decades of research have been focused on the physiological/pathophysiological events triggered by TNF-. However, the signaling network initiated by TNF- in human leukocytes is still poorly understood. In this study, we report that TNF- activates phospholipase D1 (PLD1), in a dose-dependent manner, and PLD1 is required for the activation of sphingosine kinase and cytosolic calcium signals. PLD1 is also required for NFB and ERK1/2 activation in human monocytic cells. Using antisense oligonucleotides to reduce specifically the expression of PLD isozymes showed PLD1, but not PLD2, to be coupled to TNF- signaling and that PLD1 is required to mediate receptor activation of sphingosine kinase and calcium transients. In addition, the coupling of TNF- to activation of the phosphorylation of ERK1/2 and the activation of NFB were inhibited by pretreating cells with antisense to PLD1, but not to PLD2; thus, demonstrating a specific requirement for PLD1. Furthermore, use of antisense oligonucleotides to reduce expression of PLD1 or PLD2 demonstrated that PLD1 is required for TNF--induced production of several important cytokines, such as IL-1β, IL-5, IL-6, and IL-13, in human monocytes. These studies demonstrate the critical role of PLD1 in the intracellular signaling cascades initiated by TNF- and its functional role for coordinating the signals to inflammatory responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Biomedical Research Council, Singapore.

² Address correspondence and reprint requests to Dr. Alirio J. Melendez, Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, Scotland, United Kingdom. E-mail address: A.Melendez-Romero{at}clinmed.gla.ac.uk

³ Abbreviations used in this paper: PLD, phospholipase D; SphK, sphingosine kinase.

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