Inhibitory Effects of Simvastatin on IL-33-Induced MCP-1 via the Suppression of the JNK Pathway in Human Vascular Endothelial Cells

• Published in: International journal of molecular sciences Vol. 24; no. 16; p. 13015
• Main Authors: Umebashi, Katsuyuki, Yamamoto, Masayoshi, Tokito, Akinori, Sudou, Ku, Takenoshita, Yoko, Jougasaki, Michihisa
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.08.2023; MDPI
• Subjects: Analysis; Antibodies; Antilipemic agents; Cell adhesion & migration; cell migration; Chemokines; cytokine; Endothelium; Enzyme-linked immunosorbent assay; Gene expression; Inflammation; interleukin-33; Interleukins; Investigations; Kinases; Ligands; mitogen-activated protein kinase; monocyte chemoattractant protein-1; Phosphorylation; Protein kinases; Proteins; RNA; Signal transduction; Simvastatin; Statins; Japan
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241613015

An alarmin, interleukin (IL)-33 is a danger signal that causes inflammation, inducing chemotactic proteins such as monocyte chemoattractant protein (MCP)-1 in various cells. As statins have pleiotropic actions including anti-inflammatory properties, we investigated the effects of simvastatin on IL-33-induced MCP-1 expression in human umbilical vein endothelial cells (HUVECs). HUVECs were stimulated with IL-33 in the presence or absence of simvastatin. Gene expression and protein secretion of MCP-1, phosphorylation of mitogen-activated protein kinase (MAPK), nuclear translocation of phosphorylated c-Jun, and human monocyte migration were investigated. Immunocytochemical staining and Western immunoblot analysis revealed that IL-33 augmented MCP-1 protein expression in HUVECs. Real-time reverse transcription–polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) showed that IL-33 significantly increased MCP-1 mRNA and protein secretion, which were suppressed by c-jun N-terminal kinase (JNK) inhibitor SP600125 and p38 MAPK inhibitor SB203580. Simvastatin inhibited IL-33-induced MCP-1 mRNA, protein secretion, phosphorylation of JNK and c-Jun. Additionally, the IL-33-induced nuclear translocation of phosphorylated c-Jun and THP-1 monocyte migration were also blocked by simvastatin. This study demonstrated that IL-33 induces MCP-1 expression via the JNK and p38 MAPK pathways in HUVECs, and that simvastatin inhibits MCP-1 production by selectively suppressing JNK. Simvastatin may inhibit the progression of IL-33-induced inflammation via suppressing JNK to prevent MCP-1 production.