Abstract
Inflammatory cytokines tumor necrosis factor-alpha and interleukin-1 trigger the ceramide signaling pathway, initiated by neutral sphingomyelinase-elicited hydrolysis of cell membrane phospholipid sphingomyelin to ceramide, a new lipid second messenger. Here, we show that triggering the ceramide pathway by sphingomyelinase or C2- and C6-ceramide enhances collagenase-1 (matrix metalloproteinase-1; MMP-1) gene expression by fibroblasts. C2-ceramide activates three distinct mitogen-activated protein kinases (MAPKs) in dermal fibroblasts, i.e. extracellular signal-regulated kinase 1/2 (ERK1/2), stress-activated protein kinase/Jun N-terminal-kinase (SAPK/JNK), and p38. Stimulation of MMP-1 promoter activity by C2-ceramide is dependent on the presence of a functional AP-1 cis-element and is entirely inhibited by overexpression of MAPK inhibitor, dual specificity phosphatase CL100 (MAPK phosphatase-1). Activation of MMP-1 promoter by C2-ceramide is also effectively inhibited by kinase-deficient forms of ERK1/2 kinase (MEK1/2) activator Raf-1, ERK1 and ERK2, SAPK/JNK activator SEK1, or SAPKbeta. In addition, ceramide-dependent induction of MMP-1 expression is potently prevented by PD 98059, a selective inhibitor of MEK1 activation, and by specific p38 inhibitor SB 203580. These results show that triggering the ceramide signaling pathway activates MMP-1 gene expression via three distinct MAPK pathways, i.e. ERK1/2, SAPK/JNK, and p38, and suggest that targeted modulation of the ceramide signaling pathway may offer a novel therapeutic approach for inhibiting collagenolytic activity, e.g. in inflammatory disorders.
Highlights
Tumor necrosis factor-␣ (TNF-␣) is a proinflammatory cytokine, which potently inhibits accumulation of connective tissue components
We show for the first time that triggering the ceramide pathway with neutral sphingomyelinase or cell-permeable ceramides in human skin fibroblasts results in marked stimulation of Matrix metalloproteinases (MMPs)-1 expression and that this effect is dependent on the presence of a functional AP-1 cis-element in the MMPs (2). Collagenase-1 (MMP-1) promoter region as well as on the activity of extracellular signal-regulated kinase 1/2 (ERK1/2), stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK), and p38 mitogen-activated protein kinases (MAPKs)
These results show that the effects of TNF-␣ and IL-1 on MMP-1 gene expression can be mimicked by activating the ceramide pathway in dermal fibroblasts, suggesting that targeted modulation of this pathway may offer a novel approach for therapeutic inhibition of matrix degradation, e.g. in inflammatory disorders
Summary
Tumor necrosis factor-␣ (TNF-␣) is a proinflammatory cytokine, which potently inhibits accumulation of connective tissue components. We show for the first time that triggering the ceramide pathway with neutral sphingomyelinase or cell-permeable ceramides in human skin fibroblasts results in marked stimulation of MMP-1 expression and that this effect is dependent on the presence of a functional AP-1 cis-element in the MMP-1 promoter region as well as on the activity of extracellular signal-regulated kinase 1/2 (ERK1/2), stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK), and p38 mitogen-activated protein kinases (MAPKs).
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call