Human IL-8 regulates smooth muscle cell VCAM-1 expression in response to endothelial cells exposed to atheroprone flow.
OBJECTIVE
Interleukin-8 (IL-8) is a soluble human-specific chemokine implicated in the development of the chronic inflammatory disease atherosclerosis. Recently, we showed that atheroprone hemodynamics induced IL-8 secretion from endothelial cells (ECs) concurrent with increased EC/smooth muscle cell (SMC) VCAM-1 expression in a human hemodynamic coculture model. Despite an IL-8 association with inflammation, we show here that blocking IL-8 activity during atheroprone flow resulted in increased levels of EC/SMC VCAM-1 expression. We tested the hypothesis that IL-8 limits SMC VCAM-1 expression in response to inflammatory stimuli, either atheroprone flow or cytokine interleukin-1beta (IL-1beta) addition.


RESULTS
Atheroprone flow increased monocyte adhesion in both EC/SMCs, concurrent with the induction of VCAM-1 protein. VCAM-1 antisera attenuated this response. IL-1beta upregulated VCAM-1 in SMCs by 3-fold, a response inhibited by the addition of IL-8 at 24 hours. Neither IL-1beta nor IL-8 induced proliferation or migration. Neutralization of the IL-8 receptor, CXCR2, further induced VCAM-1 in the presence of IL-1beta, and phospho-p38 was required for NF-kappaB activation and VCAM-1 expression. Additionally, IL-8 reduced p38 activation and NF-kappaB activity induced by IL-1beta alone.


CONCLUSIONS
Together, these findings provide evidence for a novel role whereby IL-8 limits the inflammatory response in ECs/SMCs via VCAM-1 modulation.
Hastings
Nicole E
NE
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
Feaver
Ryan E
RE
Lee
Monica Y
MY
Wamhoff
Brian R
BR
Blackman
Brett R
BR
D050197:Atherosclerosis / Q000503:physiopathology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D016209:Interleukin-8; D019010:Vascular Cell Adhesion Molecule-1