Matrix metalloproteinase-1 expression induced by IL-1β requires acid sphingomyelinase

Abstract 

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-1β), 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-1β-induced expression of MMP-1 is dependent on ASM.

Abbreviations: ASM, acid sphingomyelinase, ECM, extracellular matrix, ERK, extracellular signal-regulated kinase, IL-1β, interleukin-1 beta, MMP, matrix metalloproteinase, NSM, neutral sphingomyelinase, p38MAPK, p38 mitogen-activated protein kinase, SAPK/JNK, stress-activated protein kinase/Jun N-terminal kinase, SMase, sphingomyelinase, SphK, sphingosine kinase, S1P, sphingosine-1 phosphate, dhS1P, dihydrosphingosine 1-phosphate, TNF, tumor necrosis factor

Keywords: Extracellular matrix degradation, Collagen breakdown, Ceramide, Inflammation, Lipid metabolism, Imipramine