Role of FAN in Tumor Necrosis Factor-α and Lipopolysaccharide-induced Interleukin-6 Secretion and Lethality in d-Galactosamine-sensitized Mice

Abstract

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 FANdeficient 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 FANdeficient 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␣.

Dissection of the multiple mechanisms of TNF‐α‐induced apoptosis in liver injury

“…It was further found that LPSinduced elevation of serum IL-6 (but not TNF-α) was attenuated in fan-deficient mice. Interestingly, IL-6-deficient mice were also partially resistant to endotoxin-induced liver apoptosis and lethality [43]. These data suggest that FAN could contribute to the pathogenesis of the fulminant hepatitis triggered by endotoxin, possibly by regulating IL-6 secretion.…”

“…However, it does not alter some of the other TNF-α-induced other effects [42]. More importantly, fan-deficient mice were shown to confer partial protection against LPS-and TNF-α-induced liver injury [43]. It was further found that LPSinduced elevation of serum IL-6 (but not TNF-α) was attenuated in fan-deficient mice.…”

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

“…In its both reduced (GSH) and oxidized (GSSG) forms, glutathione serves as a natural inhibitor of N-SMase [25], which hydrolyzes sphingomyelin into ceramide, controlling the sphingolipid signaling cascade [26][27][28] and mediating TNF-α apoptotic [29] and negative inotropic effects in cardiomyocytes [11,30,31]. Downstream ceramide generation, the ordered cascade of events in N-SMase pathway comprises downregulation of the prosurvival factor Bcl-2, resulting into a decrease of the proapoptotic Bax/ prosurvival Bcl-2 protein ratio that in turn elicits activation of caspase-3 [32].…”

CpG DNA Prevents Liver Injury and Shock-mediated Death by Modulating Expression of Interleukin-1 Receptor-associated Kinases

“…CpG DNA/D-GalN Challenge in Vivo-Previous studies have shown that proinflammatory cytokines TNF-␣, IL-6, IL-12, and interferon ␥ play a detrimental role, whereas anti-inflammatory cytokine IL-10 plays a protective role in the acute liver injury and shock-mediated death of D-GalN-sensitized mice (30,(37)(38)(39)(40)(41). Therefore, we investigated whether CpG DNA pretreatment alters systemic and/or liver expression of these cytokines in mice challenged with CpG DNA/DGalN.…”