Interferon-γ, a Strong Suppressor of Cell Proliferation, Induces Upregulation of Keratin K6, One of the Inflammatory- and Proliferation-Associated Keratins

Keratin K6 is known as an inflammatory and hyperproliferative keratin, and is induced by an inflammatory and hyperproliferative agent. In this study, we demonstrated that interferon-γ, an antiproliferative agent, also induces keratin K6. We used normal human ex vivo skin, normal human cultured keratinocytes, HaCaT keratinocytes, and DJM cells to examine the induction of K6 by interferon-γ, by immunohistochemical staining, Western blot analysis, promoter chloramphenicol acetyl transferase assay, and reverse transcriptase polymerase chain reaction of mRNA. We succeeded in demonstrating the induction of keratin K6 by interferon-γ in ex vivo human skin and HaCaT keratinocytes at the protein and message level, and in cultured normal human keratinocytes at the promoter level. The inhibition of the signal transducing activator of transcription 1 pathway by a dominant-negative transfer gene caused the inhibition of K6 induction by interferon-γ, and the blocking of nuclear factor κB using antisense oligonucleotides also inhibited the K6 induction. We also blocked the released interleukin-1α from keratinocytes after stimulation with interferon-γ by neutralizing antibodies, which showed a decrease in the K6 induction. Our results suggest that a small amount of interleukin-1α, which cannot induce K6 by itself, is secreted upon stimulation by interferon-γ, and that the induction of K6 occurs through the synergistic effect of the interferon-γ/signal transducing activator of transcription 1 and interleukin-1α/nuclear factor κB pathways. This is the first report to describe K6 induction in epidermal keratinocytes by interferon-γ and indicate a probable signal transduction pathway, and demonstrates that K6 is a possible partner of K17 in the inflammatory process.