Matrix metalloproteinase-1 expression induced by IL-1beta requires acid sphingomyelinase.
Matrix metalloproteinase-1 (MMP-1) is increased in inflammatory conditions leading to destruction of extracellular matrix. Many inflammatory stimuli activate sphingomyelinases (SMases), which generate ceramide. We aimed to define the relevance and type of SMase responsible for the regulation of MMP-1. Acid sphingomyelinase (ASM)-deficient human fibroblasts failed to phosphorylate extracellular signal-regulated kinase (ERK), or upregulate MMP-1 mRNA and protein expression upon stimulation with interleukin-1 beta (IL-1beta), whereas phosphorylation of p38 mitogen-activated protein kinase and IL-8 production remained unaffected. Transfection of ASM restored MMP-1 production. Addition of exogenous SMase was sufficient to restore activation of ERK and increase MMP-1 mRNA. Inhibition of ASM with imipramine completely abrogated MMP-1 induction. The results suggest that IL-1beta-induced expression of MMP-1 is dependent on ASM.
Bauer
Jessica
J
Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
Huy
Christian
C
Brenmoehl
Julia
J
Obermeier
Florian
F
Bock
Jürgen
J
D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D053583:Interleukin-1beta; D016209:Interleukin-8; D012333:RNA, Messenger; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase; D020781:Matrix Metalloproteinase 1