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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

ATP-Depleting Carbohydrates Prevent Tumor Necrosis Factor Receptor 1-Dependent Apoptotic and Necrotic Liver Injury in Mice

Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Konstanz, Germany (M.L., G.K., R.L., H.H., A.W.); Department of Pharmacology, Leo Pharma A/S, Ballerup, Denmark (M.L.); Aurigon Life Science GmbH, Tutzingen, Germany (G.K.); University of Applied Sciences, Krems, Austria (R.L.); and ES Cell International Pte Ltd, Biopolis, Singapore (H.H.)

We demonstrated previously that depletion of hepatic ATP by endogenous metabolic shunting of phosphate after fructose treatment renders hepatocytes resistant to tumor necrosis factor (TNF)-induced apoptosis. We here address the question whether this principle extends to TNF receptor 1-mediated caspase-independent apoptotic and to necrotic liver injury. As in the apoptotic model of galactosamine/lipopolysaccharide (LPS)-induced liver damage, the necrotic hepatotoxicity initiated by sole high-dose LPS treatment was abrogated after depletion of hepatic ATP. Although systemic TNF and interferon- levels were suppressed, animals still were protected when ATP depletion was initiated after the peak of proinflammatory cytokines upon LPS injection, showing that fructose-induced ATP depletion affects both cytokine release and action. In T cell-dependent necrotic hepatotoxicity elicited by concanavalin A or galactosamine + staphylococcal enterotoxin B, ATP depletion prevented liver injury as well, but here without modulating cytokine release. By attenuating caspase-8 activation, ATP depletion of hepatocytes in vitro impaired TNF receptor signaling by the death-inducing signaling complex, whereas receptor internalization and nuclear factor-B activation upon TNF stimulation were unaffected. These findings demonstrate that sufficient target cell ATP levels are required for the execution of both apoptotic and necrotic TNF-receptor 1-mediated liver cell death.

Address correspondence to: Dr. Hannes Hentze, ES Cell International, 11 Biopolis Way, Helios Building #05-06, 138667 Singapore. E-mail: hhentze{at}escellinternational.com