CENTRAL ROLE OF FERROUS FERRIC IRON IN THE ULTRAVIOLET-B IRRADIATION-MEDIATED SIGNALING PATHWAY LEADING TO INCREASED INTERSTITIAL COLLAGENASE (MATRIX-DEGRADING METALLOPROTEASE (MMP)-1) AND STROMELYSIN-1 (MMP-3) MESSENGER-RNA LEVELS IN CULTURED HUMAN DERMAL FIBROBLASTS/

Reactive oxygen species (ROS) are important second messengers for the induction of several genes in a variety of physiological and pathologi cal conditions. Ultraviolet B (UVB) irradiation has recently been show n to generate lipid peroxidation products and hydroxyl radicals (HO.) with detrimental long term effects like cancer formation and premature aging of the skin, Here, we addressed the question of whether ferric/ ferrous iron via the generation of ROS may mediate the UVB response, f inally leading to connective tissue degradation, a hallmark in carcino genesis and aging. Therefore, we studied the involvement of iron and R OS in the modulation of Jun N-terminal kinase 2 (JNK2) activity, c-jun and c-fos mRNA levels, key signaling steps in the transcriptional con trol of matrix-degrading metalloprotease (MMP)-1/interstitial collagen ase and MMP-3/stromelysin-1 after-UVB irradiation of human dermal fibr oblasts in vitro. The iron-driven generation of lipid peroxides and hy droxyl radicals were identified as early events in the downstream sign aling pathway of the UVB response leading to a 15-fold increase in JNK 2 activity, a 3.5-fold increase in c-jun, to a 6-fold increase in MMP- 1, and a 3.8-fold increase in MMP-3 mRNA levels, while virtually no al teration of c-fos mRNA levels were observed. Diminished generation of reactive oxygen species resulted in a significant reduction of JNK2 ac tivity, c-jun, MMP-1, and MMP-3 mRNA levels after WE irradiation compa red with UVB-irradiated cells. Collectively, we have identified the ir on-driven Fenton reaction and lipid peroxidation as possible central m echanisms underlying signal transduction of the UVB response.