The hydroxytyrosol-dependent increase of TNF-α in LPS-activated human monocytes is mediated by PGE2 and adenylate cyclase activation

An accurate regulation of PGE2 and TNF-a production is an important event for a physiological inflammation process. We have recently reported that in LPS-activated human monocytes hydroxytyrosol, the main phenol present in extra virgin olive oil reduced both the COX-2 gene expression and PGE2 secretion while it increased the TNF-a accumulation in the culture medium. Here we have investigated whether these effects were related to each other, clarifying the possible mechanisms involved. We found that hydroxytyrosol (100 lM) increased the TNF-a mRNA level in LPS-activated human monocytes as evaluated by both RT-PCR and real time PCR (qPCR). Exogenous PGE2 reduced both TNF-a mRNA and TNF-a secretion (EIA assay) while the activation of adenylate cyclase by forskolin decreased only the TNF-a secretion but did not influence the TNF-a mRNA level. Acting similarly to non steroidal antiinflammatory drugs (NSAIDs), the hydroxytyrosol could be used to develop innovative drugs for the control of inflammation and immune response. The decrease of TNF mediated by forskolin, moreover, could suggest that the pharmacological regulation of cAMP production may represent a strategy to control the side effects of NSAIDs.