Entry #: 27
Date: 11 December 2017
Section: Inflammation
Topic: Resveratrol and hydroxytyrosol in inflammation
Type: Original article

Download PDF

OliveNetTM Journal Club

Expert review of literature related to olives and olive oil

D. Elizabeth McCord, Nancy B. Ray and Tom C. Karagiannis


Nutritionally relevant concentrations of resveratrol and hydroxytyrosol mitigate oxidative burst of human granulocytes and monocytes and the production of pro-inflammatory mediators in LPS-mediate RAW 264.7 macrophages


Bigagli et al

Citation / Year

(1) / 2017


Hydroxytyrosol, resveratrol, monocytes, macrophages, nuclear factor (erythroid-derived 2)-like 2, cyclooxygenase


Both the major olive phenolic, hydroxytyrosol and the well-known red wine phenolic, resveratrol have been shown to possess potent antioxidant and anti-inflammatory effects. Importantly, both hydroxytyrosol and resveratrol and have been shown to be absorbed into cells by passive diffusion (2, 3). Further, micromolar concentrations are achievable following oral administration extra-virgin olive oil with biodistribution of olive phenolics and their metabolites to various organs particularly the liver and kidney in humans (4). Similarly, micromolar serum concentrations of resveratrol are achieved following a single oral dose of the compound (3, 5). With respect to antioxidant and anti-inflammatory effects of dietary polyphenols such as hydroxytyrosol and resveratrol, regulation through the transcription factor nuclear factor (erythroid-like 2) – like 2 (Nrf2) pathway is important (6, 7). Apart from activation of phase 2 detoxification pathways, modulation of the heme-oxygenase 1 enzymes, and regulation of redox homeostasis, activation (nuclear translocation) of Nrf2 results in the inhibition of pro-inflammatory mediators (e.g. cytokines, cyclooxygenase 2, inducible nitric oxide synthase). The inflammatory process involves the activation of numerous microRNAs, an important one with respect to monocytes and macrophages, and regulation of Nrf2 mRNA being miRNA-146a (8, 9). Therefore, in this study the antioxidant and anti-inflammatory effects of biologically (nutritionally) relevant concentrations (up to 100 μM, with strong focus on a concentration of 10 μM) of hydroxytyrosol and resveratrol, were investigated in human granulocytes, monocytes, and in RAW 264.7 macrophages.

Key points and implications

Using a logical series of conventional cell culture studies including immunoblotting, real-time PCR and immunofluorescence, the authors investigated the effects of hydroxytyrosol and resveratrol in phorbol 12-myristate 13-acetate (PMA; 100 μM, 15 minutes) and lipopolysaccharide (LPS; 1 μg/mL, 6 or 18 hours) stimulated human granulocytes (PMA), monocytes (PMA and LPS), and in RAW 264.7 macrophages (LPS). In summary, the findings indicated that: 1) hydroxytyrosol and resveratrol reduced levels of reactive oxygen species in human granulocytes and monocytes, 2) hydroxytyrosol and resveratrol displayed anti-inflammatory effects by reducing the expression of C11b in PMA-stimulated granulocytes and monocytes, 3) resveratrol inhibited the expression of cyclooxygenase-2 and prostaglandin E2 (PGE2) in LPS stimulated RAW 264.7 macrophages; both resveratrol and hydroxytyrosol inhibited LPS-stimulated PGE2 in human monocytes, and 4) hydroxytyrosol and resveratrol activated Nrf2 (nuclear translocation) and inhbited the expression of miRNA-146a in RAW 264.7 macrophages stimulated with LPS. It is noteworthy that oleuropein, the glycoside of which is thought to require a glucose transporter for uptake into cells (10), was examined in experiments much more modest beneficial effects at 5-10 μM, compared to hydroxytyrosol and resveratrol. Overall, the findings highlight the beneficial effects of two major dietary polyphenols and more generally, the results are in line with the current understanding of the beneficial effects of polyphenol-rich diets, such as the Mediterranean diet.

Related publications

  1. E. Bigagli et al., Nutritionally relevant concentrations of resveratrol and hydroxytyrosol mitigate oxidative burst of human granulocytes and monocytes and the production of pro-inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. International immunopharmacology 43, 147-155 (2017).
  2. C. Manna et al., Transport mechanism and metabolism of olive oil hydroxytyrosol in Caco-2 cells. FEBS letters 470, 341-344 (2000).
  3. T. Walle, Bioavailability of resveratrol. Annals of the New York Academy of Sciences 1215, 9-15 (2011).
  4. M. N. Vissers, P. L. Zock, M. B. Katan, Bioavailability and antioxidant effects of olive oil phenols in humans: a review. European journal of clinical nutrition 58, 955-965 (2004).
  5. X. Vitrac et al., Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. Life sciences 72, 2219-2233 (2003).
  6. S. M. Ahmed, L. Luo, A. Namani, X. J. Wang, X. Tang, Nrf2 signaling pathway: Pivotal roles in inflammation. Biochimica et biophysica acta 1863, 585-597 (2017).
  7. J. M. Lee, J. A. Johnson, An important role of Nrf2-ARE pathway in the cellular defense mechanism. Journal of biochemistry and molecular biology 37, 139-143 (2004).
  8. K. D. Taganov, M. P. Boldin, K. J. Chang, D. Baltimore, NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proceedings of the National Academy of Sciences of the United States of America 103, 12481-12486 (2006).
  9. Y. He et al., MiR-146a regulates IL-6 production in lipopolysaccharide-induced RAW264.7 macrophage cells by inhibiting Notch1. Inflammation 37, 71-82 (2014).
  10. S. C. Edgecombe, G. L. Stretch, P. J. Hayball, Oleuropein, an antioxidant polyphenol from olive oil, is poorly absorbed from isolated perfused rat intestine. The Journal of nutrition 130, 2996-3002 (2000).