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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.

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