Journal
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
Volume 51, Issue 1, Pages 71-77Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FJC.0b013e31815bd23d
Keywords
interleukin 6; lipopolysaccharide (LPS); toll-like receptor 4; vascular smooth muscle cell
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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 I kappa B 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-kappa B or C/EBP impaired promoter activation in response to LPS. Further impairment occurred when both NF-kappa B- 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-kappa B, and C/EBP play active roles in that process.
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