Role of FAN in tumor necrosis factor-alpha and lipopolysaccharide-induced interleukin-6 secretion and lethality in D-galactosamine-sensitized mice.
Tumor necrosis factor (TNF) alpha-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 TNFalpha 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 TNFalpha-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 TNFalpha) serum concentrations was attenuated in FAN-deficient mice. A less pronounced secretion of IL-6 was also observed after LPS or TNFalpha 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 TNFalpha.
INSERM U.466, Laboratoire de Biochimie, Institut Louis Bugnard, Centre Hospitalier Universitaire Rangueil, Toulouse, France.
Sophie
S
Malagarie-Cazenave
Bruno
B
Ségui
Sophie
S
Lévêque
Virginie
V
Garcia
Stéphane
S
Carpentier
Marie-Françoise
MF
Altié
Anne
A
Brouchet
Valérie
V
Gouazé
Nathalie
N
Andrieu-Abadie
Yara
Y
Barreira
Hervé
H
Benoist
Thierry
T
Levade
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002518:Ceramides / Q000032:analysis; D004351:Drug Resistance; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005688:Galactosamine / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology* / Q000506:poisoning; D008099:Liver / Q000737:chemistry / Q000166:cytology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000502:physiology*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000506:poisoning
D002518:Ceramides; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C102036:NSMAF protein, human; C491112:Nsmaf protein, mouse; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine