title: Overexpression of Glucocorticoid-induced Leucine Zipper (GILZ) increases susceptibility to Imiquimod-induced psoriasis and involves cutaneous activation of TGF-β1.
abstract: Psoriasis vulgaris is a chronic inflammatory skin disease affecting millions of people. Its pathophysiology is complex and involves a skin compartment with epidermal and immune cells which produce cytokines, e.g. belonging to the IL-23-Th17-cell axis. Glucocorticoids (GCs) are the most common therapeutics used in cutaneous inflammatory disorders and GC-induced leucine zipper (GILZ) has emerged as a mediator of GCs due to its anti-inflammatory actions, theoretically lacking GC side-effects. We evaluated whether GILZ may provide a better therapeutic index in comparison to GCs during the onset and progression of psoriasis by generating and characterizing a mouse model with generalized overexpression of this protein (GILZ-Tg mice) and the imiquimod (IMQ) psoriasis model. Unexpectedly, in GILZ-Tg mice, the severity of IMQ-induced psoriasis-like skin lesions as well as induction of cytokines commonly up-regulated in human psoriasis (Il-17, Il-22, Il-23, Il-6, S100a8/a9, and Stat3) was significantly more pronounced relative to GILZ-Wt mice. The increased susceptibility to IMQ-induced psoriasis of GILZ-Tg mice was significantly associated with skin-specific over-activation of TGF-β1-mediated signaling via SMAD2/3. Our findings demonstrate that GILZ may behave as pro-inflammatory protein in certain tissues and that, similar to prolonged GC therapy, GILZ as an alternative treatment for psoriasis may also have adverse effects.
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas (IBV-CSIC), Jaime Roig 11, E-46010 Valencia, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Carceller
authors.affiliation: Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Marlies
authors.initials: M
authors.lastname: Ballegeer
authors.affiliation: Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.|Laboratory of Immunoregulation and Mucosal Immunology, Ghent University, B-9000 Ghent, Belgium.|Receptor Research Laboratories, Nuclear Receptor Lab, Medical Biotechnology Center Cytokine Receptor Laboratory, VIB, B-9000 Ghent, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Deckers
authors.affiliation: Department of Medicine, University of Perugia Medical School, 06132 Perugia, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
authors.affiliation: Department of Medicine, University of Perugia Medical School, 06132 Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bruscoli
authors.affiliation: Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Tino
authors.initials: T
authors.lastname: Hochepied
authors.affiliation: Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas (IBV-CSIC), Jaime Roig 11, E-46010 Valencia, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Pérez
mesh_terms: D000634:Aminoquinolines / Q000633:toxicity*; D000818:Animals; D040501:Calgranulin A / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055879:Gene Knock-In Techniques; D000077271:Imiquimod; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism; D011565:Psoriasis / Q000139:chemically induced* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D000634:Aminoquinolines; D040501:Calgranulin A; D016207:Cytokines; C498608:Dsip1 protein, mouse; D011994:Recombinant Proteins; C086145:S100a8 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000077271:Imiquimod