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J. Biol. Chem., Vol. 279, Issue 18, 18648-18655, April 30, 2004

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Role of FAN in Tumor Necrosis Factor- and Lipopolysaccharide-induced Interleukin-6 Secretion and Lethality in D-Galactosamine-sensitized Mice^*

Sophie Malagarie-Cazenave, Bruno Ségui, Sophie Lévêque, Virginie Garcia, Stéphane Carpentier, Marie-Françoise Altié, Anne Brouchet, Valérie Gouazé, Nathalie Andrieu-Abadie, Yara Barreira, Hervé Benoist, and Thierry Levade¶

From the INSERM U.466, Laboratoire de Biochimie and the Animal Facility, Institut Louis Bugnard, Centre Hospitalier Universitaire Rangueil, 31059 Toulouse, France

Tumor necrosis factor (TNF) -induced neutral sphingomyelinase-mediated generation of ceramide, a bioactive lipid molecule, is transduced by the adaptor protein FAN, which binds to the intracellular region of the CD120a TNF receptor. FAN-deficient mice do not exhibit any gross abnormality. To further explore the functions of FAN in vivo and because CD120a-deficient mice are resistant to endotoxin-induced liver failure and lethality, we investigated the susceptibility of FAN-deficient animals to lipopolysaccharide (LPS). We show that after D-galactosamine sensitization, FAN-deficient mice were partially resistant to LPS- and TNF-induced lethality. Although LPS challenge resulted in a hepatic ceramide content lower in mutant mice than in control animals, it triggered similar histological alterations, caspase activation, and DNA fragmentation in the liver. Interestingly, LPS-induced elevation of IL-6 (but not TNF) serum concentrations was attenuated in FAN-deficient mice. A less pronounced secretion of IL-6 was also observed after LPS or TNF treatment of cultured peritoneal macrophages and embryonic fibroblasts isolated from FAN-deficient mice, as well as in human fibroblasts expressing a mutated FAN. Finally, we show that D-galactosamine-sensitized IL-6-deficient mice were partially resistant to endotoxin-induced liver apoptosis and lethality. These findings highlight the role of FAN and IL-6 in the inflammatory response initiated by endotoxin, implicating TNF.

Received for publication, December 30, 2003 , and in revised form, February 6, 2004.

^* This work was supported by INSERM. 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.

Recipient of fellowships from Association pour la Recherche sur la Sclérose en Plaques and Fondation pour la Recherche Médicale.

^¶ To whom correspondence should be addressed: INSERM U.466, Laboratoire de Biochimie, Institut Louis Bugnard, CHU Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse cedex 9, France. Tel.: 33-561-32-20-60; Fax: 33-561-32-20-84; E-mail: levade{at}toulouse.inserm.fr or levade.t{at}chu-toulouse.fr.

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