Roles of MAPK and NF-κB in Interleukin-6 Induction by Lipopolysaccharide in Vascular Smooth Muscle Cells

• DOI: 10.1097/fjc.0b013e31815bd23d
• Publication Date: 2009-03-05T06:35:12Z
• Authors: Yong-Hae Son; Yeon-Tae Jeong; Kyeong-Ah Lee; Kyung-Ha Choi; Sun-Mi Kim; Byung-Yong Rhim; Koanhoi Kim
• Keywords: Lipopolysaccharides; Mitogen-Activated Protein Kinase 1; 0301 basic medicine; Mitogen-Activated Protein Kinase 3; Transcription, Genetic; Interleukin-6; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Toll-Like Receptor 4; 03 medical and health sciences; CCAAT-Enhancer-Binding Proteins; Humans; Mitogen-Activated Protein Kinases; Aorta; Cells, Cultured; Signal Transduction

Toll-like receptor (TLR)-4 signaling promotes cytokine synthesis in vascular smooth muscle cells (VSMC). However, it is unknown how TLR-4 regulates interleukin-6 (IL-6) in VSMC. Therefore, the present study investigated cellular factors involved in TLR-4-mediated IL-6 in VSMC in terms of MAPK and transcription elements. Exposure of aortic smooth muscle cells to TLR4-specific lipopolysaccharide (LPS) not only enhanced IL-6 release but also induced IL-6 transcript via promoter activation. The promoter activation was attenuated by dominant-negative MKK1 and to a lesser extent by dominant-negative MKK3, but not by dominant-negative MKK4. IL-6 promoter activity was diminished by U0126 or SB202190, but not by SP600125. Co-transfection with dominant negative CCAAT/enhancer binding protein or with IkappaB suppressed LPS-induced promoter activation, whereas the promoter activity was not influenced by dominant negative c-Jun. Mutation in the IL-6 promoter region at the binding site of NF-kappaB or C/EBP impaired promoter activation in response to LPS. Further impairment occurred when both NF-kappaB- and C/EBP-binding sites were mutated. LPS-induced IL-6 promoter activation was also prevented by pretreatment with epigallocatechin 3-gallate, curcumin, and resveratrol. The present study reports that TLR4-agonistic LPS induces IL-6 through transcriptional activation in VSMC and ERK1/2, p38 MAPK, NF-kappaB, and C/EBP play active roles in that process.