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.
Copyright © 2011 Wiley-Liss, Inc.
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