title: Preclinical studies of a specific PPARγ modulator in the control of skin inflammation.
abstract: Peroxisome proliferator-activated receptor γ (PPARγ) antagonizes inflammatory signals by interfering with NF-κB nuclear translocation. Consistently, PPARγ agonists have been proposed in various inflammatory skin disorders, but their wide use has been limited by severe side effects. Classes of compounds with specific PPARγ agonism have been designed to selectively target inflammatory pathways. Among these compounds, GED-0507-34L has been developed and recently used in phase II clinical trials for inflammatory bowel diseases. This study was aimed at assessing the role of GED-0507-34L in preclinical models of inflammatory skin diseases. The compound modulated PPARγ function and suppressed the inflammatory process inhibiting NF-κB nuclear translocation with the consequent reduction of inflammatory cytokines expression, such as IL-6, IL-8, IL-12, IL-21, IL-23, tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) in normal human keratinocytes and lymphocytes treated with lipopolysaccharide (LPS) or TNF-α. Moreover, an altered proliferation and expression of differentiation markers induced by TNF-α were also counteracted. In psoriasis-like skin lesions elicited in mice by IL-21, topical application of GED-0507-34L reduced cellular infiltrate and epidermal hyperplasia, normalizing the differentiation process. The results indicate that GED-0507-34L possesses anti-inflammatory properties useful for the management of patients with inflammatory skin diseases including psoriasis. Phase I trial on patients is ongoing.
authors.affiliation: Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Mastrofrancesco
authors.affiliation: Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kovacs
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Sarra
authors.affiliation: Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Bastonini
authors.affiliation: Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Cardinali
authors.affiliation: Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy.
authors.forename: Nicaela
authors.initials: N
authors.lastname: Aspite
authors.affiliation: Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Camera
authors.affiliation: Laboratoire de Chimie Thérapeutique, Faculté des Sciences Pharmaceutiques et Biologiques, Université Lille-Nord de France, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavatte
authors.affiliation: University Lille Nord de France, Inserm U995, Huriez Hospital, Hepato-Gastroenterology Department, Lille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Desreumaux
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
authors.affiliation: Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy. Electronic address: picardo@ifo.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Picardo
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D000814:Aniline Compounds / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D001706:Biopsy; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D015603:Keratinocytes / Q000166:cytology; D008070:Lipopolysaccharides / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D010666:Phenylpropionates / Q000737:chemistry / Q000627:therapeutic use*; D011422:Propionates / Q000737:chemistry / Q000627:therapeutic use*; D011485:Protein Binding; D011565:Psoriasis / Q000378:metabolism; D034622:RNA Interference; D012867:Skin / Q000187:drug effects / Q000473:pathology*
chemical_list: C000588557:3-(4-aminophenyl)-2-methoxypropionic acid; D000814:Aniline Compounds; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047495:PPAR gamma; D010666:Phenylpropionates; D011422:Propionates; C107446:2-methoxypropanoic acid; D051546:Cyclooxygenase 2