Abstract
FoxO1 transcription factor controls the glucose and lipid metabolism, as well as cell proliferation and stress response. Akt, activated by insulin and other growth factors, phosphorylates FoxO1 causing its nuclear export and activity suppression. In this manuscript, we show that IL-1β, a pro-inflammatory cytokine, has the opposite effects on FoxO1. IL-1β stimulation of primary rat hepatocytes and HEK293 cells overexpressing the IL-1β receptor (293-IL-1RI) results in increased nuclear and cytosolic FoxO1 protein but not mRNA levels. IL-1β stimulation also elevates the levels of a mutant FoxO1 that is resistant to Akt phosphorylation. This suggests that an Akt-independent mechanism is involved. Co-stimulation with insulin does not affect the IL-1β induction of FoxO1. The IL-1β effects on FoxO1 are counteracted, however, by the silencing or inhibition of neutral sphingomyelinase 2 (nSMase-2) using shRNAi, scyphostatin, or GW4869, as well as by the pharmacological inhibition of JNK and ERK. Reversely, the overexpression of nSMase-2 through adenovirus-mediated gene transfer potentiates, in a JNK- and ERK-dependent manner, the IL-1β effects. We also show that transcription of insulin-like growth factor-binding protein-1 mRNA, which requires active FoxO1, is stimulated by IL-1β and is suppressed by the inhibition of nSMase-2 and JNK. In conclusion, we propose that IL-1β regulates FoxO1 activity through a novel nSMase-2-dependent pathway.
Highlights
The FoxO1 transcription factor, which controls the hepatic metabolism, is regulated through Akt-mediated phosphorylation
We show that stimulation of hepatocytes with the pro-inflammatory cytokine IL-1 leads to increased FoxO1 nuclear content through an Akt-independent mechanism involving neutral sphingomyelinase-2 and ceramide
We show that transcription of insulin-like growth factor-binding protein-1 mRNA, which requires active FoxO1, is stimulated by IL-1 and is suppressed by the inhibition of nSMase-2 and JNK
Summary
The FoxO1 transcription factor, which controls the hepatic metabolism, is regulated through Akt-mediated phosphorylation. We show that transcription of insulin-like growth factor-binding protein-1 mRNA, which requires active FoxO1, is stimulated by IL-1 and is suppressed by the inhibition of nSMase-2 and JNK. The mechanism of MAP kinase activation by IL-1 involves activation of neutral sphingomyelinase 2 (nSMase-2) and the generation of ceramide at the plasma membrane [7, 8] The latter is required for the proper activation of the JNK arm of the IL-1 signaling pathway because it regulates the phosphorylation and ubiquitination of IRAK-1 [9]. JNK-mediated signaling has emerged as an alternative pathway for FoxO1 regulation and apparently counteracts insulin- and growth factor-mediated pathways It is unknown whether physiological inducers of JNK such as pro-inflammatory cytokines can regulate FoxO1 nuclear export and/or retention. Considering the role of FoxO1 in regulating hepatic lipid protein and glucose metabolism, our study indicates the existence of novel pathways by which IL-1 (and inflammation in general) can influence the basic metabolic functions of an organism
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