Divergent gene regulation and growth effects by NF-κB in epithelial and mesenchymal cells of human skin

NF-kappaB regulates normal and pathological processes, including neoplasia, in a tissue-context-dependent manner. In skin, NF-kappaB is implicated in epidermal homeostasis as well as in the pathogenesis of squamous cell carcinoma; however, its function in the underlying mesenchymal dermis has been unclear. To gain insight into NF-kappaB roles in these two adjacent cutaneous tissue compartments, NF-kappaB effects on expression of 12 435 genes were determined in epidermal keratinocytes and dermal fibroblasts. Although NF-kappaB induced proinflammatory and antiapoptotic genes in both settings, it exhibited divergent effects on growth regulatory genes. In keratinocytes, but not in fibroblasts, NF-kappaB induced p21(CIP1), which was sufficient to inhibit growth of both cell types. Levels of growth inhibitory factor (GIF), in contrast, were increased by NF-kappaB in both settings but inhibited growth only in keratinocytes. These findings indicate that transcription factors such as NF-kappaB can program tissue-selective effects via both differential target gene induction as well as by inducing common targets that exert differing effects depending on cellular lineage.