title: 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.
authors: Hampton University Skin of Color Research Institute (HUSCRI), Hampton, VA, USA.
authors: Alon
authors: A
authors: Mantel
authors: Hampton University Skin of Color Research Institute (HUSCRI), Hampton, VA, USA.
authors: Austin
authors: A
authors: Newsome
authors: Hampton University Skin of Color Research Institute (HUSCRI), Hampton, VA, USA.
authors: Theresa
authors: T
authors: Thekkudan
authors: Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School (EVMS), Norfolk, VA, USA.
authors: Robert
authors: R
authors: Frazier
authors: Hampton University Skin of Color Research Institute (HUSCRI), Hampton, VA, USA.|Department of Dermatology, Eastern Virginia Medical School (EVMS), Norfolk, VA, USA.
authors: Meena
authors: M
authors: Katdare
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism*; D007150:Immunohistochemistry; D007627:Keloid / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000196:embryology; D000072105:Superoxide Dismutase-1 / Q000378:metabolism
chemical_list: C477819:15-deoxyprostaglandin J2; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; C037112:9-deoxy-delta-9-prostaglandin D2; D003094:Collagen; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000072105:Superoxide Dismutase-1; C505407:CASP3 protein, human; D053148:Caspase 3; D015230:Prostaglandin D2
keywords: P38-MAPK; aldo-keto reductase 1C3; fibrosis; keloid; prostaglandin