The IFN-gamma-dependent suppressor of cytokine signaling 1 promoter activity is positively regulated by IFN regulatory factor-1 and Sp1 but repressed by growth factor independence-1b and Krüppel-like factor-4, and it is dysregulated in psoriatic keratinocytes.
Epidermal keratinocytes can counteract the detrimental effects of IFN-gamma by inducing the expression of suppressor of cytokine signaling (SOCS)1, which plays an important anti-inflammatory and self-protective role. To date, limited information exists on its expression and regulation in human diseased keratinocytes. In this study, we compared the expression levels of SOCS1 in keratinocytes isolated from skin affected by psoriasis with cells obtained from healthy donors, unveiling that keratinocytes are more prone than healthy cells to upregulate SOCS1 mRNA expression in response to IFN-gamma. We explored the regulatory mechanisms involved in socs1 gene transcription, and found that Sp1 and IFN regulatory factor-1 transcription factors are, respectively, responsible for the basal and IFN-gamma-induced activity of human socs1 promoter. In parallel, we demonstrated that socs1 promoter is negatively regulated by two transcriptional repressors, namely, growth factor independence-1b and Krüppel-like factor 4, which tightly control SOCS1 transcription on IFN-gamma stimulation. Interestingly, although the expression of Sp1 and IFN regulatory factor-1 activators of socs1 promoter is unaltered, growth factor independence-1b and Krüppel-like factor 4 are significantly reduced in psoriatic compared with healthy keratinocytes. This reduction and the consequent unbalanced binding of transcriptional activators and repressors to socs1 promoter after IFN-gamma stimulation might be responsible for the enhanced expression of SOCS1 in psoriatic cells. We suggest that SOCS1 exaggerated upregulation in psoriatic keratinocytes could represent a mechanism through which these cells attempt to protect themselves from IFN-gamma effects. However, the SOCS1 increased levels in psoriatic keratinocytes are not sufficient to completely inhibit the expression of proinflammatory genes.
Madonna
Stefania
S
Laboratorio di Immunologia Sperimentale, Istituto Dermopatico dell'Immacolata, Rome, Italy.
Scarponi
Claudia
C
Sestito
Rosanna
R
Pallotta
Sabatino
S
Cavani
Andrea
A
Albanesi
Cristina
C
D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011565:Psoriasis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D004268:DNA-Binding Proteins; C111977:GFI1B protein, human; D050856:Interferon Regulatory Factor-1; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D016329:Sp1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; D008156:Luciferases