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.

Mastrofrancesco, A., Kovacs, D., Sarra, M., Bastonini, E., Cardinali, G., Aspite, N., et al. (2014). Preclinical studies of a specific PPARγ modulator in the control of skin inflammation. JOURNAL OF INVESTIGATIVE DERMATOLOGY, 134(4), 1001-1011 [10.1038/jid.2013.448].

Preclinical studies of a specific PPARγ modulator in the control of skin inflammation

MONTELEONE, GIOVANNI;
2014-01-01

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.
2014
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/12 - GASTROENTEROLOGIA
English
2708; Biochemistry; Cell Biology; Molecular Biology
NF-kappa B; Active Transport, Cell Nucleus; Animals; Cyclooxygenase 2; Skin; Humans; Aniline Compounds; Mice; Biopsy; Cell Proliferation; Protein Binding; Propionates; Inflammation; Epidermis; Phenylpropionates; Psoriasis; Cells, Cultured; PPAR gamma; Mice, Inbred C57BL; Lipopolysaccharides; Cytokines; Keratinocytes; RNA Interference; Cell Adhesion
Mastrofrancesco, A., Kovacs, D., Sarra, M., Bastonini, E., Cardinali, G., Aspite, N., et al. (2014). Preclinical studies of a specific PPARγ modulator in the control of skin inflammation. JOURNAL OF INVESTIGATIVE DERMATOLOGY, 134(4), 1001-1011 [10.1038/jid.2013.448].
Mastrofrancesco, A; Kovacs, D; Sarra, M; Bastonini, E; Cardinali, G; Aspite, N; Camera, E; Chavatte, P; Desreumaux, P; Monteleone, G; Picardo, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/89841
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