title: Peroxisome-proliferator-activated receptor (PPAR)-gamma activation stimulates keratinocyte differentiation.
abstract: Previous studies demonstrated that peroxisome-proliferator-activated receptor (PPAR)-alpha or PPAR-delta activation stimulates keratinocyte differentiation, is anti-inflammatory, and improves barrier homeostasis. Here we demonstrate that treatment of cultured human keratinocytes with ciglitazone, a PPAR-gamma activator, increases involucrin and transglutaminase 1 mRNA levels. Moreover, topical treatment of hairless mice with ciglitazone or troglitazone increases loricrin, involucrin, and filaggrin expression without altering epidermal morphology. These results indicate that PPAR-gamma activation stimulates keratinocyte differentiation. Additionally, PPAR-gamma activators accelerated barrier recovery following acute disruption by either tape stripping or acetone treatment, indicating an improvement in permeability barrier homeostasis. Treatment with PPAR-gamma activators also reduced the cutaneous inflammatory response that is induced by phorbol 12-myristate-13-acetate, a model of irritant contact dermatitis and oxazolone, a model of allergic contact dermatitis. To determine whether the effects of PPAR-gamma activators are mediated by PPAR-gamma, we next examined animals deficient in PPAR-gamma. Mice with a deficiency of PPAR-gamma specifically localized to the epidermis did not display any cutaneous abnormalites on inspection, but on light microscopy there was a modest increase in epidermal thickness associated with an increase in proliferating cell nuclear antigen (PCNA) staining. Key functions of the skin including permeability barrier homeostasis, stratum corneum surface pH, and water-holding capacity, and response to inflammatory stimuli were not altered in PPAR-gamma-deficient epidermis. Although PPAR-gamma activators stimulated loricrin and filaggrin expression in wild-type animals, however, in PPAR-gamma-deficient mice no effect was observed indicating that the stimulation of differentiation by PPAR-gamma activators is mediated by PPAR-gamma. In contrast, PPAR-gamma activators inhibited inflammation in both PPAR-gamma-deficient and wild-type mouse skin, indicating that the inhibition of cutaneous inflammation by these PPAR-gamma activators does not require PPAR-gamma in keratinocytes. These observations suggest that thiazolidindiones and perhaps other PPAR-gamma activators maybe useful in the treatment of cutaneous disorders.
authors.affiliation: Department of Dermatology, University of California, San Francisco and VA Medical Center, San Francisco, California 94121, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Mao-Qiang
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Fowler
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
authors.forename: Peggy
authors.initials: P
authors.lastname: Lau
authors.forename: Sandra
authors.initials: S
authors.lastname: Chang
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Brown
authors.forename: Arthur H
authors.initials: AH
authors.lastname: Moser
authors.forename: Liliane
authors.initials: L
authors.lastname: Michalik
authors.forename: Beatrice
authors.initials: B
authors.lastname: Desvergne
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Pierre H
authors.initials: PH
authors.lastname: Chambon
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D017453:Dermatitis, Irritant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000473:pathology; D005260:Female; D000091344:Filaggrin Proteins; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008822:Mice, Transgenic; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D011503:Transglutaminases / Q000235:genetics
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007004:Hypoglycemic Agents; D011498:Protein Precursors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; C032253:involucrin; D011503:Transglutaminases; C105804:transglutaminase 1; C039671:ciglitazone