p21WAF1 Is Required for Interleukin-16-Induced Migration and Invasion of Vascular Smooth Muscle Cells via the p38MAPK/Sp-1/MMP-9 Pathway

• Published in: PloS one 2015-11, Vol.10 (11), p.e0142153-e0142153
• Main Authors: Park, Sung Lyea, Hwang, Byungdoo, Lee, Sun-Young, Kim, Won Tae, Choi, Yung Hyun, Chang, Young-Chae, Kim, Wun-Jae, Moon, Sung-Kwon
• Format: Article
• Language: English
• Subjects: Activation; Activator protein 1; Animals; Arteriosclerosis; Atherosclerosis; Binding; Blockage; CD4 antigen; CD4 Antigens - metabolism; Cell adhesion & migration; Cell Movement - drug effects; Cell Movement - physiology; Cell Proliferation; Cells, Cultured; Complications and side effects; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-dependent kinases; Development and progression; Gelatinase B; Imidazoles - pharmacology; Immune response; Inhibitors; Interleukin 16; Interleukin-16 - metabolism; Interleukin-16 - pharmacology; Interleukins; Kinases; Leukocyte migration; Lymphocytes; MAP Kinase Signaling System; Matrix Metalloproteinase 9 - metabolism; Medical treatment; Muscles; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - immunology; Myocytes, Smooth Muscle - physiology; NF-κB protein; Nutrition; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Patient outcomes; Phosphorylation; Physiological aspects; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; Rats; Regulators; RNA, Small Interfering - genetics; Signaling; siRNA; Smooth muscle; Sp1 Transcription Factor - metabolism; Stenosis; Transcription factors; Vascular diseases
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0142153

Interleukin-16 (IL-16) is a lymphocyte chemoattractant factor well known for its role in immune responses, but its role in vascular disease is unknown. Here, we explored the novel physiological function of IL-16 in vascular smooth muscle cells (VSMCs). The expression of IL-16 and its receptor CD4 was observed in VSMCs. Treatment with IL-16 enhanced the migration and invasion by VSMCs without altering the proliferative potential. IL-16 induced MMP-9 expression via the binding activity of transcription factors NF-κB, AP-1, and Sp-1 motifs in VSMCs. Among the relevant signaling pathways examined, only p38MAPK phosphorylation was significantly stimulated in IL-16-treated VSMCs. Treatment with p38MAPK inhibitor SB203580 prevented the IL-16-induced migration and invasion of VSMCs. SB203580 treatment inhibited the MMP-9 expression and activation of Sp-1 binding in IL-16-treated VSMCs, and siRNA knockdown of CD4 expression blocked the induction of migration, invasion, p38MAPK phosphorylation, MMP-9 expression, and Sp-1 binding activation stimulated by IL-16. The IL-16 induced cell-cycle-inhibitor p21WAF1 expression in VSMCs, but had no effect on the expression levels of other cell-cycle negative regulators. Finally, blockage of p21WAF1 function with specific siRNA abolished the IL-16-induced elevation of migration, invasion, p38MAPK phosphorylation, MMP-9 expression, and Sp-1 binding activation in VSMCs. Taken together, p21WAF1 was required for the induction of p38MAPK-mediated MMP-9 expression via activation of the Sp-1 binding motif, which led to migration and invasion of VSMCs interacting with IL-16/CD4. These results could provide that IL-16 is a new target in the treatment of vascular diseases such as atherosclerosis and re-stenosis.