Fatty acids as metabolic mediators in innate immunity


Prof. Dr Andreas Schäffler, MD, Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany. Tel.: +49-941-944-7009; fax: +49-941-944-7019; e-mail: andreas.schaeffler@klinik.uni-regensburg.de


Background  Increasing data support the hypothesis of a local and systemic crosstalk between adipocytes and monocytes mediated by fatty acids. The aim of this study was to characterize the immunomodulatory effects of a large panel of fatty acids on cytokines and chemokines in monocytic THP-1 cells and primary human monocytes. We tested whether anti-inflammatory fatty acids are able to inhibit the binding of lipopolysaccharide (LPS) to its receptor, toll-like receptor/MD-2 (TLR4/MD-2).

Materials and methods  Resistin, monocyte chemoattractant protein-1 (MCP-1) and tumour necrosis factor (TNF) were measured by enzyme-linked immunosorbent assay. Proteins were analysed by Western blot. A designed Flag-tagged TLR4/MD-2 fusion protein (LPS trap) was used to investigate the effect of fatty acids on binding of LPS to its receptor. In 30 patients with type 2 diabetes mellitus (T2D), the correlation of serum triglyceride levels with LPS-induced monocyte activation was analysed.

Results  Eleven fatty acids investigated exerted differential effects on the monocytic release of cytokines and chemokines. Eicosapentaenoic acid had potent anti-inflammatory effects on human primary monocytes and THP-1 cells; 100 and 200 μM eicosapentaenoic acid dose-dependently inhibited LPS binding to the LPS trap. LPS-induced release of monocytic MCP-1 and TNF was significantly and positively correlated with serum triglyceride levels in 30 patients with T2D.

Conclusions  Monocytic activation is differentially regulated by fatty acids and depends on triglyceride levels in T2D. The main finding of the present study shows that eicosapentaenoic acid inhibits the specific binding of LPS to TLR4/MD-2. Eicosapentaenoic acid represents a new anti-inflammatory LPS-antagonist.