This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sortino, M. A. Articles by Canonico, P. L. Search for Related Content PubMed PubMed Citation Articles by Sortino, M. A. Articles by Canonico, P. L.

Tumor Necrosis Factor- Induces Apoptosis in Immortalized Hypothalamic Neurons: Involvement of Ceramide-Generating Pathways

Institutes of Pharmacology and Respiratory Diseases (C.V.), University of Catania School of Medicine, 95125 Catania; and the Department of Internal Medicine, Section of Pharmacology, University of Pavia (P.L.C.), Pavia, Italy

Address all correspondence and requests for reprints to: Dr. Maria Angela Sortino, Institute of Pharmacology, University of Catania School of Medicine, Viale Andrea Doria 6, 95125 Catania, Italy. E-mail: msortino{at}mbox.unict.it

To investigate possible effects that may contribute, together with a direct action on neurohormone secretion, to the impairment of gonadal axis function during inflammation, we evaluated the effect of TNF on the growth and viability of GT1–7 hypothalamic neurons and the intracellular transduction pathways involved in these effects. TNF caused a reduction of cell number and an induction of apoptotic death. These effects were mimicked by cell-permeable analogs of ceramide and by neutral or acidic sphingomyelinase. Exposure to acidic sphingomyelinase induced a persistent (up to 48 h) reduction of cell growth and apoptosis, whereas the effect of neutral sphingomyelinase was time limited. The involvement of acidic sphingomyelinase in TNF action was demonstrated by the partial prevention of ceramide generation, apoptosis, and reduced cell growth by the inhibitor of the acidic sphingomyelinase-generating pathway, D609, whereas the involvement of ceramide was proved by complete prevention of TNF-induced effects by treatment with okadaic acid at concentrations inhibiting ceramide-dependent protein phosphatase. The present data indicate that TNF, through activation of ceramide-generating pathways, is able to affect GT1–7 cell viability, suggesting an additional effect that may contribute to the global action of this cytokine on neuroendocrine activities.

This article has been cited by other articles:

				K. Strle, S. R. Broussard, R. H. McCusker, W.-H. Shen, R. W. Johnson, G. G. Freund, R. Dantzer, and K. W. Kelley Proinflammatory Cytokine Impairment of Insulin-Like Growth Factor I-Induced Protein Synthesis in Skeletal Muscle Myoblasts Requires Ceramide Endocrinology, October 1, 2004; 145(10): 4592 - 4602. [Abstract] [Full Text] [PDF]

				K. M. Dhandapani, M. Hadman, L. De Sevilla, M. F. Wade, V. B. Mahesh, and D. W. Brann Astrocyte Protection of Neurons: ROLE OF TRANSFORMING GROWTH FACTOR-{beta} SIGNALING VIA A c-Jun-AP-1 PROTECTIVE PATHWAY J. Biol. Chem., October 31, 2003; 278(44): 43329 - 43339. [Abstract] [Full Text] [PDF]

				T. A. Jackson, D. M. Koterwas, M. A. Morgan, and A. P. Bradford Fibroblast Growth Factors Regulate Prolactin Transcription via an Atypical Rac-Dependent Signaling Pathway Mol. Endocrinol., October 1, 2003; 17(10): 1921 - 1930. [Abstract] [Full Text] [PDF]

				K. W. Hong, K. Y. Kim, H. K. Shin, J. H. Lee, J. M. Choi, Y.-G. Kwak, C. D. Kim, W. S. Lee, and B. Y. Rhim Cilostazol Prevents Tumor Necrosis Factor-{alpha}-Induced Cell Death by Suppression of Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation and Activation of Akt/Cyclic AMP Response Element-Binding Protein Phosphorylation J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 1182 - 1190. [Abstract] [Full Text] [PDF]

				I. W. Jeffrey, M. Bushell, V. J. Tilleray, S. Morley, and M. J. Clemens Inhibition of Protein Synthesis in Apoptosis: Differential Requirements by the Tumor Necrosis Factor {alpha} Family and a DNA-damaging Agent for Caspases and the Double-stranded RNA-dependent Protein Kinase Cancer Res., April 1, 2002; 62(8): 2272 - 2280. [Abstract] [Full Text] [PDF]

				S.-N. Wu, Y.-K. Lo, B. I.-T. Kuo, and H.-T. Chiang Ceramide Inhibits the Inwardly Rectifying Potassium Current in GH3 Lactotrophs Endocrinology, November 1, 2001; 142(11): 4785 - 4794. [Abstract] [Full Text] [PDF]

				K. Hallermalm, K. Seki, C. Wei, C. Castelli, L. Rivoltini, R. Kiessling, and J. Levitskaya Tumor necrosis factor-{alpha} induces coordinated changes in major histocompatibility class I presentation pathway, resulting in increased stability of class I complexes at the cell surface Blood, August 15, 2001; 98(4): 1108 - 1115. [Abstract] [Full Text] [PDF]

				C. K. Combs, J. C. Karlo, S.-C. Kao, and G. E. Landreth {beta}-Amyloid Stimulation of Microglia and Monocytes Results in TNF{alpha}-Dependent Expression of Inducible Nitric Oxide Synthase and Neuronal Apoptosis J. Neurosci., February 15, 2001; 21(4): 1179 - 1188. [Abstract] [Full Text] [PDF]