Sequential DNA damage-independent and -dependent activation of NF-κB by UV

NF-kappa B activation in response to UV irradiation of HeLa cells or of primary human skin fibroblasts occurs with two overlapping kinetics but totally different mechanisms. Although both mechanisms involve induced dissociation of NF-kappa B from I kappa B alpha and degradation of I kappa B alpha, targeting for degradation and signaling are different. Early I kappa B alpha degradation at 30 min to similar to 6 h is not initiated by UV-induced DNA damage. It does not require I kappa B kinase (IKK), as shown by introduction of a dominant-negative kinase subunit, and does not depend on the presence of the phosphorylatable substrate, I kappa B alpha, carrying serines at positions 32 and 36. Induced I kappa B alpha degradation requires, however, intact N- (positions 1-36) and C-terminal (positions 277-287) sequences. I kappa B degradation and NF-kappa B activation at late time points, 15-20 h after UV irradiation, is mediated through DNA damage-induced cleavage of IL-1 alpha precursor, release of IL-1 alpha and autocrine/paracrine action of IL-1 alpha. Late-induced I kappa B alpha requires the presence of Ser32 and Ser36. The late mechanism indicates the existence of signal transfer from photoproducts in the nucleus to the cytoplasm. The release of the 'alarmone' IL-1 alpha may account for some of the systemic effects of sunlight exposure.