UVB activation of NF-kappaB in normal human keratinocytes occurs via a unique mechanism

The transcription factor nuclear factor-kappaB (NF-kappaB) is comprised of a family of proteins that are implicated in a wide variety of cellular functions, including the control of cell proliferation, cell survival, and cellular differentiation. Although NF-kappaB is activated in response to inflammatory signals or cellular stress, in the skin NF-kappaB is also implicated to play a role in normal epidermal homeostasis. Often the cellular consequences of NF-kappaB activation are dependent on the specific triggering stimuli. Thus, we have compared the activation mechanism and the function of NF-kappaB following two common stimuli of normal human keratinocytes, inflammatory mediators (tumor necrosis factor alpha (TNFalpha)), and cellular stress (ultraviolet light B (UVB) irradiation). These experiments indicate that although both TNFalpha and UVB stimulate NF-kappaB DNA-binding activity in normal human keratinocytes, the mechanisms of NF-kappaB activation by each stimulus is different. In contrast to the NF-kappaB response following TNFalpha, activation of NF-kappaB by UVB is independent of Ikappa Balpha degradation. Analyses of NF-kappaB-dependent gene expression following TNFalpha or UVB treatment demonstrate that each of these stimulatory signals results in a specific subset of genes that are activated or repressed. These studies provide further evidence of the stimuli and cell-type specific nature of NF-kappaB function.