IFN-gamma-dependent IL-7 gene regulation in keratinocytes

IL-7 plays a central role in regulating the growth and differentiation of T cells. We have reported previously that epidermal keratinocytes produce biologically relevant amounts of IL-7, thereby supporting the growth of epidermal gamma delta T cells. In this report, we report that IL-7 gene expression is regulated in keratinocytes by IFN-gamma. Treatment of Pam 212 keratinocytes with IFN-gamma induced a preferential expression of 2.6- and 1.5-kb IL-7 mRNAs, in addition to the 2.9- and 1.7-kb mRNAs that are expressed constitutively. The 2.6- and 1.5-kb mRNAs are produced through the use of alternative transcription initiation sites; these mRNAs are transcribed within 250 bp from the coding sequence, whereas 2.9- and 1.7-kb mRNAs contain > 400 bases in the 5'-untranslated region. IFN-gamma appears to promote this conversion through the IFN-stimulated response element (ISRE), which is located 270 bp upstream from the coding sequence. ISRE is followed by the initiator, a non-TATA-type transcription control element. Functional relevance of the ISRE/initiator complex was suggested by the observations that IFN-gamma-dependent transcription was initiated from immediately downstream of this complex, and that its deletion resulted in an abrogated IFN-gamma responsiveness in transcriptional regulation. These results document a novel mechanism by which IL-7 gene expression is regulated in keratinocytes by a cytokine produced by T cells (IFN-gamma).