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Abstract
Background
Atherosclerosis is based on a chronic inflammatory process including the innate and adaptive immune response. Costimulatory molecules and their receptors provide decisive signals for antigen-specific cell activation. The contribution of B7-related pathways to atherosclerosis has hardly been explored.
Methods
In the present study, we investigated the contribution of B7-1 to inflammation and tissue injury in the human plaque microenvironment in order to identify possible target structures of future therapeutic agents ex vivo and in vitro.
Results
Carotid artery plaque stimulation with lipopolysaccharides (LPS) could be significantly inhibited by RhuDex®, a specific inhibitor of the costimulatory molecule B7-1 ex vivo (P<0.001). Coculture of antigen-presenting cells with T-cells demonstrated that the inhibitory effects of RhuDex® derived from reduced T-cell activation. In addition, incubation of monocytes/macrophages with LPS and RhuDex® resulted in an inhibitory negative feedback on antigen-presenting cells. Signaling pathways affected by RhuDex® seem to be nuclear transcription factor kappa B, activator protein-1, and extracellular signal-regulated kinase 1/2.
Conclusion
The present data support B7-1 alone as an important costimulatory molecule in the context of LPS-mediated inflammation in atherosclerotic lesions. Due to its marked inhibitory effects, RhuDex® may be a useful therapy to modulate the inflammatory milieu in atherosclerosis.
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Acknowledgments
We thank Nadine Wambsganss for excellent technical assistance. This work was supported by a stipend from the German Academic Exchange Service to Li Zhao and by a research grant from Medigene AG to Christian Erbel.
Disclosure
The authors report no conflicts of interest in this work. Andreas O Doesch received a grant from Deutsche Forschungsgemeinschaft and Ruprecht-Karls-Universität Heidelberg within the funding program Open Access Publishing.