title: Therapeutical potential of a peptide mimicking the SOCS1 kinase inhibitory region in skin immune responses.
abstract: IFN-γ-activated keratinocytes are key contributors to the pathogenetic mechanisms leading to type-1 immune-mediated skin disorders. In these epidermal cells, SOCS1 negatively regulates the molecular cascades triggered by IFN-γ by disabling JAK2 phosphorylation through its kinase inhibitory region (KIR). Aimed at potentiating the SOCS1 inhibitory function on JAK2/STAT1 axis in keratinocytes, we recently developed a set of peptides mimicking the SOCS1 KIR domain, which are capable of efficiently binding JAK2 in vitro. Here, the effects of one such SOCS1 KIR mimetic named PS-5 on IFN-γ-activated human keratinocytes were evaluated. We found that IFN-γ-activated keratinocytes treated with PS-5 exhibited impaired JAK2, IFN-γRα, and STAT1 phosphorylation. We also observed reduced levels of the IRF-1 transcription factor, and a strong reduction in ICAM-1, HLA-DR, CXCL10, and CCL2 inflammatory gene expression. ICAM-1 reduced expression resulted in an impaired adhesiveness of T lymphocytes to autologous keratinocytes. Consistently, the migration of T cells toward supernatants from PS-5-treated keratinocytes was drastically reduced. Finally, PS-5 treatment hampered STAT1 activation and the expression of STAT1-dependent inflammatory genes in IFN-γ-treated explants of human skin. These data collectively indicate that PS-5 has an important therapeutic potential in the treatment of type-1 immune-mediated skin diseases.
authors.affiliation: Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Madonna
authors.forename: Claudia
authors.initials: C
authors.lastname: Scarponi
authors.forename: Nunzianna
authors.initials: N
authors.lastname: Doti
authors.forename: Teresa
authors.initials: T
authors.lastname: Carbone
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavani
authors.forename: Pasqualina Liana
authors.initials: PL
authors.lastname: Scognamiglio
authors.forename: Daniela
authors.initials: D
authors.lastname: Marasco
authors.forename: Cristina
authors.initials: C
authors.lastname: Albanesi
mesh_terms: D032701:Biomimetics; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology; D009842:Oligopeptides / Q000276:immunology* / Q000494:pharmacology; D009924:Organ Culture Techniques; D034622:RNA Interference; D054340:Receptors, KIR / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D012867:Skin / Q000187:drug effects* / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014162:Transfection
chemical_list: D009842:Oligopeptides; C583287:PS-5 peptide; D054340:Receptors, KIR; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins
keywords: Epidermal keratinocytes; IFN-γ-signaling; SOCS1; Skin inflammation