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

Abstract

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.

MICAL2 promotes breast cancer cell migration by maintaining epidermal growth factor receptor (EGFR) stability and EGFR/P38 signalling activation

“…Stimulation of the P38 kinase cascade leads to HSP27 phosphorylation, then the phosphorylated HSP27 is released from the plus end of the actin filament, and these processes are important for actin reorganization and cell motility . In addition, the activation of P38 in response to chemical stressors induces cell invasiveness, which is reported to be associated with increased MMP9 secretion . In this study, several lines of evidence indicated that MICAL2 promoted breast cancer cell migration at least partially through EGFR/P38 signalling pathway.…”

Melatonin suppresses TPA‐induced metastasis by downregulating matrix metalloproteinase‐9 expression through JNK/SP‐1 signaling in nasopharyngeal carcinoma

“…Regulation of MMP‐9 expression might be controlled through its transcription factors, particularly SP‐1, AP‐1, NF‐κB, and polyomavirus enhancer activator (PEA). For example, hydroquinone stimulates MMP‐9 expression through AP‐1, kindlin‐2 promotes MMP‐9 expression through NF‐κB in prostate cancer, the cell cycle inhibitor p21WAF‐1 regulates MMP‐9 expression through p38/SP‐1 pathway, and PEA‐3 is necessary for MMP‐9 regulation in ovarian cancer . Hence, we used the luciferase assay to examine MMP‐9 promoter activity; the results showed that melatonin suppresses MMP‐9 promoter activity through the SP‐1 region of HONE‐1 and NPC‐39 cells.…”

Electronegative low‐density lipoprotein of patients with metabolic syndrome induces pathogenesis of aorta through disruption of the stimulated by retinoic acid 6 cascade

“…For blocking non‐specific antigen, the PVDF membrane was immersed in Tris‐buffered saline 0.2% Tween 20 (TBS‐T) and 5% skim milk at 4°C overnight. Then, the PVDF membrane was immersed in TBS‐T containing 5% skim milk and primary antibodies for detecting L5 receptor (LOX1), STRA6 signaling (STRA6, CRBP1, RARα and RXRα), phosphorylation of atherogenic p38MAPK (p‐p38MAPK and p38MAPK) and Smads pathway (pSmad2 and Smad2), and markers of atherogenesis (TGFβ 1 , caspase 3 and MMP9) in aortic cells. After washing with TBS‐T, the PVDF membrane was immersed in TBS‐T containing 5% skim milk and a 1:10,000 dilution of horseradish peroxidase‐conjugated antibody.…”