C/EBPβ Deficiency Enhances Keratinocyte Apoptosis after UVB-Induced DNA Damage via Regulation of the Type I IFN and TNF Responses

Numerous IFN-I stimulated genes were up-regulated in UVB-treated C/EBPβ-/- keratinocytes, including genes that regulate extrinsic apoptosis. Inhibition of the interferon / receptor or the associated kinase Tyk2 greatly reduced cell death in UVB-exposed C/EBPβ deficient keratinocytes, demonstrating the dependence of IFN signaling in C/EBPβ regulated apoptosis. The apoptosis inducing cytokine, tumor necrosis factor alpha (TNF-α) was identified as one of the most significant upstream regulators activated in UVB exposed C/EBPβ-/- keratinocytes compared to UVB exposed wild type control.

UVB exposed C/EBPβ-/- keratinocytes displayed increased expression of TNF-α and the enhanced apoptosis in C/EBPβ-/- keratinocytes was suppressed by a TNF-α neutralizing antibody. Our results indicate that loss of C/EBPβ enhances activation of a non-canonical UVB DNA damage response pathway involving interferon and TNF signaling to induce keratinocyte cell death.