The role of aldo‐keto reductase 1C3 (AKR1C3)‐mediated prostaglandin D2 (PGD2) metabolism in keloids

Abstract

Keloids are progressively expanding scars, mostly prevalent in individuals of African descent. Previous data identified increased mast cell number and activation state in keloids suggesting a role in disease progression. The major eicosanoid secreted by mast cells is prostaglandin D2 (PGD2), a relatively unstable pro-inflammatory mediator which can be spontaneously converted to 15-deoxy-(Delta12,14)-prostaglandin J2(15d-PGJ2) or enzymatically metabolized to 9α,11β-PGF2 by aldo-keto reductase 1C3 (AKR1C3). In this work, we investigated the possible role of PGD2 and its metabolites in keloids using CRL1762 keloid fibroblasts (KF) and immunohistochemical staining. Our data suggested approximately 3-fold increase of tryptase-positive mast cell count in keloids compared with normal skin. Furthermore, AKR1C3 was overexpressed in the fibrotic area of keloids while relatively weak staining detected in normal skin. Metabolism of PGD2 to 9α,11β-PGF2 by both, KF and normal fibroblasts, was dependent on AKR1C3 as this reaction was attenuated in the presence of the AKR1C3 inhibitor, 2'-hydroxyflavanone, or in cells with decreased AKR1C3 expression. 15d-PGJ2, but not the other tested PGs, inhibited KF proliferation, attenuated KF-mediated collagen gel contraction and increased caspase-3 activation. In addition, treatment with 15d-PGJ2 activated P38-MAPK, induced reactive oxygen species and upregulated superoxide dismutase-1 (SOD-1). Finally, inhibition of P38-MAPK further augmented 15d-PGJ2-induced caspase-3 cleavage and attenuated its effect on SOD-1 transcription. This work suggests that localized dual inhibition of AKR1C3 and P38-MAPK may inhibit keloid progression. Inhibiting AKR1C3 activity may generate oxidative environment due to redirection of PGD2 metabolism towards 15d-PGJ2 while inhibition of P38-MAPK will sensitize keloid cells to ROS-induced apoptosis.

Expression of AKR1C3 Protein in Human Keloid Skin Tissue

“…Previous studies found increased levels of ROS in keloids and proposed their implication in the pathogenesis of keloids [17]. Evidence of ROS accumulation supports the hypothesis that oxidative stress is a mechanism of cellular proapoptotic actions in keloid cells [18].…”

The 15d‑PGJ2 hydrogel ameliorates atopic dermatitis through suppression of the immune response

“…Furthermore, 15d-PGJ 2 was found to inhibit a series of fibroblast-associated processes, such as TGF-β stimulation of collagen gene expression, transdifferentiation of myofibroblasts (30) as well as the Smad-dependent promoter activity (31). 15d-PGJ 2 has also been shown to attenuate the proliferation of keloid cells, inhibit collagen gel contraction as well as to increase cleavage of caspase-3 (32). It has been demonstrated, however, that 15d-PGJ 2 and a prostanoid DP2 receptor agonist (13,14-dihydro-15-keto-prostaglandin D2) had no clear effect on the scratching behavior of rodents, thus suggesting that such prostaglandin D2 suppressive effect ought to be mediated by the prostanoid DP1 receptor instead (33).…”

The Roles of Various Prostaglandins in Fibrosis: A Review

“…PGD2 is a relatively unstable lipid with a half-life of approximately 30 min in plasma and can be metabolized to other types, including PGF2α, 9α,11β-PGF2 and the J series of PGs (such as PGJ2, Δ12-PGJ2, and 15d-PGJ2) [ 13 ]. Moreover, 15d-PGJ2, a natural ligand that activates peroxisome proliferator-activated receptor (PPAR-γ), inhibits the NF-κB pathway and induces oxidative stress, is an important lipid participating in various biological and pathological conditions [ 56 , 57 ]. A stereoisomer of PGF2α, 9α,11β-PGF2, which is metabolized from PGD2 by the enzyme PGD 11-ketoreductase, has been shown to mediate various biological activities, such as the contraction of bronchial smooth muscle cells, inhibition of platelet aggregation and induction of chemoattraction of various immune cells [ 56 ].…”

“…An increasing body of in vivo or in vitro evidence has shown that 15d-PGJ2 possesses antifibrotic properties in various experimental models, most of which occur in a PPAR-γ-independent manner. Alon et al showed that 15d-PGJ2 in keloids attenuates keloid cell proliferation, inhibits collagen gel contraction, and increases cell apoptosis by inducing oxidative stress in vitro [ 56 ]. AKR1C3 is an enzyme that metabolizes PGD2 to 9α,11 β-PGF2, the inhibition of which increases the concentration of 15d-PGJ2 and is a potential treatment for skin keloids [ 56 ].…”

“…Alon et al showed that 15d-PGJ2 in keloids attenuates keloid cell proliferation, inhibits collagen gel contraction, and increases cell apoptosis by inducing oxidative stress in vitro [ 56 ]. AKR1C3 is an enzyme that metabolizes PGD2 to 9α,11 β-PGF2, the inhibition of which increases the concentration of 15d-PGJ2 and is a potential treatment for skin keloids [ 56 ]. P38 mitogen-activated protein kinase (MAPK) is an important downstream molecule of the TGF-β signaling pathway that mediates fibrosis.…”