Role of NF-κB in the apoptotic-resistant phenotype of keratinocytes

Several studies point to a role for NF-kappa B in modulating epidermal thickness and apoptotic susceptibility of keratinocytes. When phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) are topically applied, prominent epidermal thickening occurs, and exposure to interferon (IFN)-gamma promotes increased epidermal thickness producing psoriatic lesions, While keratinocytes derived from psoriatic plaque resist apoptosis, and combination of TPA and IFN-gamma activates NF-kappa B, the molecular mechanism linking NE-kappa B activation and keratinocyte apoptosis resistance was unknown. Therefore, we examined the ability of IFN-gamma plus TPA to influence NF-kappa B activity, gene expression, and response to UV light-induced apoptosis, These responses in normal keratinocytes were compared with immortalized keratinocytes (HaCaT cells). Exposure of normal keratinocytes to IFN-gamma plus TPA produced a synergistic activation: of NF-kappa B, compared with when each reagent was used individually. Normal keratinocytes when exposed to IFN-gamma plus TPA acquired a resistance to UV light-induced apoptosis, which was dependent on NF-kappa B because expression of a dominant negative form of I kappa B alpha overcame the resistance. Compared with normal keratinocytes, HaCaT cells have a dysfunctional constitutive NF-kappa B signaling pathway not induced by IFN-gamma and TPA, rendering HaCaT cells highly susceptible to W-induced apoptosis, Thus, immortalized HaCaT cells have an abnormal constitutive and dysfunctional NF-kappa B signaling system. These results provide evidence that activation and proper regulation of NF-kappa B is essential for acquisition of an apoptotic-resistant phenotype for epidermal-derived keratinocytes.