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

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. J. Cell. Physiol. 226: 3303–3315, 2011. © 2011 Wiley Periodicals, Inc.