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Krüppel-like Factor 6 (KLF6) Affects the Promoter Activity of the 1-Proteinase Inhibitor Gene

¹From the Department of Ophthalmology, University Hospital, Centre Hospitalier Universitaire (CHU), Clermont-Ferrand, France; ²ARDEMO (Auvergne Rétinoïdes Developpement Morphogénèse) and ⁴Biochemistry and Molecular Biology Laboratory, Faculty of Medicine, University of Auvergne, Clermont-Ferrand, France; the ³Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago College of Medicine, Chicago, Illinois.

PURPOSE. Keratoconus is a progressive disease that thins and scars the cornea. In keratoconus corneas, levels of degradative enzymes, including lysosomal acid phosphatase (LAP) and cathepsin B, are elevated, and those of inhibitors 1-proteinase inhibitor (1-PI) and 2-macroglobulin (2-M) are reduced. The present study explored the possible involvement in keratoconus of Krüppel-like factor 6 (KLF6), a transcription factor previously described to be essential for the integrity of the corneal epithelium. The transcript and proteins level of KLF6 and its action in regulating the genes affected in keratoconus were examined in this study.

METHODS. Semiquantitative RT-PCR, Western blot analysis, immunofluorescence and in situ hybridization were used to investigate the expression of KLF6 mRNA and protein in normal and keratoconus corneas. Modulation by KLF6 of the promoter activity of 1-PI, LAP, cathepsin B, and 2-M genes was studied after transient transfection of KLF6 expression plasmid into corneal epithelial cells using promoter–reporter gene assays. Chromatin immunoprecipitation (ChIP) assays were performed to confirm the interactions between KLF6 and promoters of the genes affected in keratoconus.

RESULTS. A global increased expression of the transcription factor KLF6 in terms of mRNAs and proteins was observed in total cornea and/or the epithelium in a substantial number of the keratoconus specimens. The promoter activity of the human 1-PI gene was suppressed by expression of KLF6 in corneal epithelial cells. The ChIP assay confirmed a physical interaction between KLF6 and the 1-PI promoter.

CONCLUSIONS. Transcription factor KLF6 downregulates the 1-PI gene in corneal epithelial cells and may thereby be involved in keratoconus.

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