15-Deoxy-Δ 12,14-Prostaglandin J2 Exerts Pro- and Anti-Inflammatory Effects in Mesangial Cells in a Concentration-Dependent Manner

Alma      E. Martinez; Francisco      J. Sanchez-Gomez; Beatriz      Diez-Dacal; Clara      L. Oeste; Dolores      Perez-Sala

Abstract

Cyclopentenone prostaglandins play a modulatory role in inflammation, in part through their ability to covalently modify key proinflammatory proteins. Using mesangial cells as a cellular model of inflammation we have observed that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) exerts a biphasic effect on cell activation by cytokines, with nanomolar concentrations eliciting an amplification of nitric oxide (NO) production and iNOS and COX-2 levels, and concentrations of 5 μM and higher inhibiting proinflammatory gene expression. An analog of 15d-PGJ2 lacking the cyclopentenone structure (9,10-dihydro-15d-PGJ2) showed reduced ability to elicit both types of effects, suggesting that the electrophilic nature of 15d-PGJ2 is important for its biphasic action. Interestingly, the switch from stimulatory to inhibitory actions occurred within a narrow concentration range and correlated with the ability of 15d-PGJ2 to induce heme oxygenase 1 and γ-GCSm expression. These events are highly dependent on the triggering of the antioxidant response, which is considered as a sensor of thiol group modification. Indeed, the levels of the master regulator of the antioxidant response Nrf2 increased upon treatment with concentrations of 15d-PGJ2 above 5 μM, an effect that could not be mimicked by 9,10-dihydro-15d-PGJ2. Thus, an interplay of redox and electrophilic signalling mechanisms can be envisaged by which 15d-PGJ2, as several other redox mediators, could contribute both to the onset and to the resolution of inflammation in a context or concentration-dependent manner.

Keywords: 15d-PGJ2, antioxidant response, cyclopentenone prostaglandins, inflammation, inflammatory resolution, nitric oxide, Nrf2, Rat mesangial cells, redox mediators, cytokines