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

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-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) 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-PGJ(2) lacking the cyclopentenone structure (9,10-dihydro-15d-PGJ(2)) showed reduced ability to elicit both types of effects, suggesting that the electrophilic nature of 15d-PGJ(2) 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-PGJ(2) 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-PGJ(2) above 5 μM, an effect that could not be mimicked by 9,10-dihydro-15d-PGJ(2). Thus, an interplay of redox and electrophilic signalling mechanisms can be envisaged by which 15d-PGJ(2), as several other redox mediators, could contribute both to the onset and to the resolution of inflammation in a context or concentration-dependent manner.

Mitochondrial Dynamics Associated with Oxygen-Glucose Deprivation in Rat Primary Neuronal Cultures

“…Data on the drug’s effect is, nevertheless, controversial. The PGJ 2 can induce or inhibit cell proliferation/angiogenesis [39], [40], can decrease [38], [41], [42] or activate [41] inflammatory response, and can increase cell survival following some injuries [21], [43] but not others [20], [44]. The Mdivi-1, which is known to inhibit Drp1effectiveness [45], [46], did not change protein expression or cell viability in our experiments.…”

Obesity, immunomodulation and chronic kidney disease

“…As illustrated in Figure 1, 15Δ-PGJ2 may similarly to the SPMs contribute to the resolution of inflammation [6,54]. It is thus noteworthy that 15Δ-PGJ2 was recently shown to induce HO-1 expression and increase antioxidant response though Nrf2 in mesangial cells [55]. Annexin-1 has also been shown to be protective in ischemia-reperfusion injury in the rat [56], although to our knowledge its effect as of yet has not been determined in CKD.…”

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins

“…cyPGs bind to and modulate transcription factors (Cernuda-Morollón et al, 2001;Kim and Surh, 2006;Pérez-Sala, 2011), activate the antioxidant response (Levonen et al, 2004;Martínez et al, 2012), inactivate detoxifying enzymes like glutathione transferases (Sánchez-Gómez et al, 2010), and induce antiinflammatory and antiproliferative effects , for which they have been proposed as therapeutic tools (Fukushima et al, 2001;Homem de Bittencourt et al, 2007).…”