A native steroid hormone derivative triggers the resolution of inflammation

Inflamed tissues produce both prostaglandins (PGs) and 7α-hydroxylated derivatives of native circulating 3β-hydroxysteroids. These 7α-hydroxysteroids are in turn transformed into 7β-hydroxylated epimers by 11β-hydroxysteroid dehydrogenase type 1 in the tissue. 7β-Hydroxy-epiandrosterone (7β-hydroxy-EpiA) affects PG production in two models of inflammation, dextran sodium sulfate-induced colitis in the rat and TNF-α-induced activation of PG production and PG synthase expression in cultured human peripheral blood monocytes (hPBMC). Treatment with 7β-hydroxy-EpiA led to a shift from high to low colonic PGE2 levels and from low to high 15-deoxy-Δ12-14-PGJ2 (15d-PGJ2) levels, together with changes in the expression of the respective PG synthases and resolution of colonic inflammation. Addition of 7β-hydroxy-EpiA to hPBMC also changed the expression of PG synthases and decreased PGE2 while increasing 15d-PGJ2 production. These effects were only observed with 7β-hydroxy-EpiA and not with 7α-hydroxy- or 7β-hydroxy-dehydroepiandrosterone (7α-hydroxy-DHEA and 7β-hydroxy-DHEA). 15d-PGJ2, which is the native ligand for peroxisome proliferator-activated receptor subtype γ, contributes to cell protection and to the resolution of inflammation. Our results therefore suggest that 7β-hydroxy-EpiA may facilitate inflammatory resolution by shifting PG production from PGE2 to PGD2 and 15d-PGJ2. The finding that 7β-hydroxy-EpiA was effective at nM concentrations, whereas the two structurally closely related hydroxysteroids 7α-hydroxy-DHEA and 7β-hydroxy-DHEA were inactive suggests that the effects of 7β-hydroxy-EpiA are specific to this steroid and may be mediated by a specific receptor.