Author/Editor		Strle, Klemen; Broussard, Suzanne R; McCusker, Robert H; Shen, Wen-Hong; Johnson, Rodney W; Freund, Gregory G; Dantzer, Robert; Kelley, Keith W
Title		Proinflammatory cytokine impairment of insulin-like growth factor I-induced protein synthesis in skeletal muscle myoblasts requires ceramide
Type		članek
Source		Endocrinology
Vol. and No.		Letnik 145, št. 10
Publication year		2004
Volume		str. 4592-602
Language		eng
Abstract		GH and IGF-I control over 80% of postnatal growth. We recently established that TNFalpha impairs the ability of IGF-I to increase protein synthesis and promote expression of myogenin in myoblasts. Here we extend these results by showing that ceramide, a second messenger in both TNFalpha and IL-1beta receptor signaling pathways, is a key downstream sphingosine-based lipid that leads to IGF-I resistance. A cell-permeable ceramide analog, C2-ceramide, inhibits IGF-I-induced protein synthesis by 65% and blocks the ability of IGF-I to increase expression of two key myogenic factors, myogenin and MyoD. Identical results were obtained with both TNFalpha and IL-1beta (1 ng/ml). Consistent with these data, neutral sphingomyelinase (N-SMase), an enzyme that catalyzes formation of ceramide from sphingomyelin, blocks IGF-I-induced protein synthesis and expression of both myogenin and MyoD. The possibility that cytokine-induced ceramide production is required for disruption of IGF-I biologic activity was confirmed by treating C2C12 myoblasts with inhibitors of all three ceramide-generating pathways. A N-SMase inhibitor, glutathione, as well as an acidic sphingomyelinase (A-SMase) inhibitor, D609, reverse the cytokine inhibition of IGF-I-induced protein synthesis by 80% and 45%, respectively. Likewise, an inhibitor of de novo ceramide synthesis, FB1, causes a 50% inhibition. Similarly, all three inhibitors significantly impair the ability of both TNFalpha and IL-1beta to suppress IGF-I-driven expression of myogenin. These experiments establish that ceramide, derived both from sphingomyelin and de novo synthesis, is a key intermediate by which proinflammatory cytokines impair the ability of IGF-I to promote protein synthesis and expression of critical muscle-specific transcription factors.
Descriptors		ANIMALS CELL LINE CERAMIDES CYTOKINES DRUG SYNERGISM INFLAMMATION MEDIATORS INSULIN-LIKE GROWTH FACTOR I INTERLEUKIN-1 MICE MUSCLE PROTEINS MUSCLE, SKELETAL MYOD PROTEIN MYOGENIN PHOSPHOPROTEINS PHOSPHORYLATION RECOMBINANT PROTEINS SPHINGOMYELIN PHOSPHODIESTERASE TYROSINE