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.

journal_name

Eur J Immunol

authors

Madonna S,Scarponi C,Doti N,Carbone T,Cavani A,Scognamiglio PL,Marasco D,Albanesi C

doi

10.1002/eji.201343370

subject

Has Abstract

pub_date

2013-07-01 00:00:00

pages

1883-95

issue

7

eissn

0014-2980

issn

1521-4141

journal_volume

43

pub_type

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