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Am J Physiol Heart Circ Physiol (January 23, 2009). doi:10.1152/ajpheart.01158.2008
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Submitted on November 3, 2008
Revised on January 15, 2009
Accepted on January 15, 2009

Interaction of vascular smooth muscle cells and monocytes by soluble factors synergistically enhances interleukin-6 and MCP-1 production

Li Chen1, Adrian Frister1, Song Wang1, Andreas Ludwig2, Hagen Behr1, Susanna Pippig1, Beibei LI1, Andreas Simm1, Britt Hofmann1, Claudia Pilowski1, Susanne Koch1, Michael Buerke, Stefan Rose-John3, Karl Werdan4, and Harald Loppnow1*

1 Martin-Luther-Universität Halle-Wittenberg
2 Universitätsklinikum Aachen
3 Biochemisches Institut, Christian-Albrechts-Universitt
4 University Halle- Wittenberg

* To whom correspondence should be addressed. E-mail: harald.loppnow{at}medizin.uni-halle.de.

Inflammatory mechanisms contribute to atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) are potent mediators of inflammation. Both contribute to early atherogenesis by luring monocytes and regulating cell functions in the vessel wall. MCP-1 and IL-6 production resulting from interaction of invading monocytes with local vessel wall cells may accelerate atherosclerosis. We investigated the influence of the interaction of human vascular smooth muscle cells (SMC) with human mononuclear cells (MNC) or monocytes on the IL-6 and MCP-1 production in a coculture model. Interaction synergistically enhanced IL-6 and MCP-1 production (up to 30- and 10-fold, respectively), as compared with separately cultured cells. This enhancement was mediated by CD14-positive monocytes. It was depending on the SMC to MNC/monocyte ratio and as few as 0.2 monocytes per SMC induced the synergism. The synergistic IL-6 production was observed at the protein, mRNA and functional level. It was mediated by soluble factors, and simultaneous inhibition of IL-1, TNF-{alpha} and IL-6 completely blocked the synergism. IL-1, TNF and IL-6 were present in the cultures. Blockade of the synergism by sgp130Fc/sIL-6R, as well as induction of synergistic IL-6 production by costimulation of SMC with IL-1, TNF and hyper-IL-6, suggested the involvement of IL-6 trans-signalling. The contribution of IL-6 was consistent with enhanced STAT3 phosphorylation. The present data suggest that SMC/monocyte interaction may augment the pro-inflammatory status in the tissue, contributing to acceleration of early atherogenesis






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