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. 2013 Jul;43(7):1883-95.
doi: 10.1002/eji.201343370. Epub 2013 May 28.

Therapeutical potential of a peptide mimicking the SOCS1 kinase inhibitory region in skin immune responses

Stefania Madonna  1 , Claudia Scarponi, Nunzianna Doti, Teresa Carbone, Andrea Cavani, Pasqualina Liana Scognamiglio, Daniela Marasco, Cristina Albanesi
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Free article

Therapeutical potential of a peptide mimicking the SOCS1 kinase inhibitory region in skin immune responses

Stefania Madonna et al. Eur J Immunol. 2013 Jul.
Free article

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.

Keywords: Epidermal keratinocytes; IFN-γ-signaling; SOCS1; Skin inflammation.

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