Interleukin-18/WNT1-inducible signaling pathway protein-1 signaling mediates human saphenous vein smooth muscle cell proliferation

J Cell Physiol. 2011 Dec;226(12):3303-15. doi: 10.1002/jcp.22676.

Abstract

We demonstrate for the first time that the pro-inflammatory cytokine interleukin (IL)-18 stimulates rapid and significant proliferation of SMC derived from human saphenous vein (VSMC), but not coronary artery. IL-18 also stimulates VSMC growth. Further investigations revealed that IL-18-induced VSMC proliferation was Wnt inducible secreted protein-1 (WISP1) dependent. In addition to inducing its own expression via phosphatidylinositol 3-kinase/Akt-dependent IKK/NF-κB activation, IL-18 stimulated glycogen synthase kinase 3β phosphorylation and degradation, β-catenin nuclear translocation and stabilization, T-cell factor-lymphoid enhancer binding factor (TCF-LEF) activation, and WISP1 induction. Moreover, WISP1 induced its own expression, and that of survivin and multiple matrix metalloproteinases via β-catenin/TCF-LEF interaction. WISP1 also activated AP-1, but not NF-κB, and induced matrix metalloproteinase (MMP)9 transcription in part via AP-1. Interestingly, WISP1 failed to regulate tissue inhibitors of matrix metalloproteinases (TIMP) expression. These novel findings indicate that IL-18 induces a series of signaling events that result in WISP1-mediated VSMC proliferation, survival and MMP induction that are key components of vein graft stenosis and this may be amplified by IL-18 and WISP1 autoregulation and cross-regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • CCN Intercellular Signaling Proteins
  • Cell Proliferation*
  • Cells, Cultured
  • Coronary Vessels / metabolism
  • Coronary Vessels / pathology
  • Gene Expression Regulation, Enzymologic
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Hyperplasia
  • I-kappa B Kinase / metabolism
  • Inflammation Mediators / metabolism*
  • Interleukin-18 / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Mutation
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • NF-kappa B
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphorylation
  • Protein Stability
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Recombinant Proteins / metabolism
  • Saphenous Vein / metabolism
  • Saphenous Vein / pathology
  • Signal Transduction
  • Time Factors
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic
  • Transfection
  • beta Catenin / metabolism

Substances

  • CCN Intercellular Signaling Proteins
  • CCN4 protein, human
  • CTNNB1 protein, human
  • Inflammation Mediators
  • Interleukin-18
  • Intracellular Signaling Peptides and Proteins
  • Lymphoid Enhancer-Binding Factor 1
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Transcription Factor AP-1
  • beta Catenin
  • Phosphatidylinositol 3-Kinase
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • I-kappa B Kinase
  • Glycogen Synthase Kinase 3
  • Matrix Metalloproteinase 9