Resveratrol distinctively modulates the inflammatory profiles of immune and endothelial cells

Joseph Schwager, Nathalie Richard, Franziska Widmer, Daniel Raederstorff

The phenolic substance resveratrol (RES) is a plant metabolite known to modulate numerous physiological functions and to exert beneficial effects as a cancer-chemopreventing agent and on neurological, hepatic, and cardiovascular systems. Since the compound affects the lifespan of yeast and flies it might be an anti-aging substance. Mechanistically, RES is involved in down regulating the inflammatory response. The pleiotropic effects of RES in cells of the immune and endothelial system were examined in this study. Murine macrophages (RAW264.7 cells), human monocytic/leukemia cells (THP-1), PBLs and HUVECs were incubated with RES and activated with inflammatory stimuli such as LPS or TNF-α. Inflammatory mediators and adhesion molecules were measured by multiplex analysis and gene expression was quantified by RT-PCR. In PBLs, which were activated with LPS, RES blunted the production of TNF-α, CCL2/MCP-1, CCL5/RANTES, CXCL8/IL-8, whereas it increased the production of IL-1β, IL-6, CCL4/MIP-1β and CXCL10/IP-10. Thus, in the blood compartment chemokines attracting mainly monocytes were up-regulated by RES, while those attracting T lymphocytes or neutrophils were diminished. At conditions of endothelial dysfunction (ED), RES reduced the expression of cytokines, chemokines, ICAM and GM-CSF in TNF-α activated HUVECs, whereas eNOS expression was corrected to pre-ED homeostasis. In macrophages nitric oxide, PGE2, cytokines (TNF-α, IL-1β, IL-6) and chemokines (CCL2/MCP-1, CCL4/MIP-1β, CCL5/RANTES, CXCL10/IP-10) were reduced by the phenolic substance. RES had cell-specific and context-dependent effects, in particular on the expression of IL-1β, IL-6, CCL4/MIP-1β and CXCL10/IP-10. It enhanced cellular features that mirror increased alertness to disturbed immune homeostasis in the vascular-endothelial compartment (e.g. increased production of IL-1β or IL-6), whereas it blunted inflammatory mediators in macrophages and consequently chronic inflammation. We infer from the present in vitro study, that RES has unique properties in the regulation of inflammatory and immune responses, which are controlled in a complex hierarchical and temporal order.