The Endogenous Photoprotective Mechanisms In The Skin

UV-induced photo skin aging is primarily mediated via generation of reactive oxygen species/free radicals. Free radical theory of aging and skin aging is one of the most common causes of chronological and photo skin aging. UV irradiation not only activate aging process in the skin, but also activate the endogenous protective mechanisms to prevent UV-induced skin alterations including counteract or slow down photo aging process and/or to prevent skin cancer.

UV induced apoptosis is the internal mechanisms for protecting and preventing skin cancer. UV induced apoptosis mechanism is mainly transduced and activated via p53 signaling. p53 is a tumor suppressor protein functions as a tumor suppressor and is a transcription factor that is involved in cancer prevention. p53 has been described as “the guardian of the genome” because of its role in conserving stability by preventing genome mutation. In skin, p53 is activated when epidermal skin cells are damaged by UV radiation. p53 signaling activates mechanism of protection for skin cancer via cell cycle regulation and apoptosis. Upon DNA damage by acute UV radiation, p53 is induced and transcriptionally activated. Posttranscriptional activation of p53 is by phosphorylation of various serine residues. Various protein kinase including kinases in MAPK signal transduction pathway are involved in the phosphorylation of various p53 serine residues in response to UV radiation. The accumulation of the activated p53 protein result in the observation that G1 phase of cell cycle is prolonged; cell cycle regulatory proteins such as CDKs and cyclins are increased; and cyclin-dependent kinases inhibitors (CDKIs) are decreased. These changes in cell cycle regulation may provide mechanism for the cell to trigger and enter apoptosis with extensive DNA damage. If the DNA damage caused by UV radiation is very severe and the repair mechanism in response to UV induced DNA damage will not function to proceed to the DNA replication S phase of the cell cycle, apoptotic pathways are activated to eliminate damaged cells. Protein p53 as a transactivator of transcription can induce apoptosis by activating pro-apoptotic genes such as Bax and Fas and deregulating the anti-apoptotic gene bcl-2. Fas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. The cytoplasmic redistribution of apoptotic receptor Fas to the cell surface and Fas-Fas ligand interaction results in the cleavage and activation of procaspase-3,8,9, a group of proteases essential for the degradation of proteins and cellular components of the apoptotic cell. There are two types of apoptotic caspases: initiator (apical) caspases and effector (executioner) caspases. Initiator caspases (e.g., CASP2, CASP8, CASP9, and CASP10) cleave inactive pro-forms of effector caspases, thereby activating them. Effector caspases (e.g., CASP3, CASP6, CASP7) in turn cleave other protein substrates within the cell in the apoptotic process.

The skin consists of a network of natural antioxidants which include antioxidants enzymes such as superoxide dismutase, catalase and glutathione peroxidase and nonenzymatic antioxidants (e.g. vitamin E, coenzyme Q10, ascorbate, carotenoids). (see post “The Antioxidant Enzymes Network of The Skin” and “The Nonenzymatic Antioxidant Systems In Aging Skin”). These antioxidants provide protection from ROS produced during cellular metabolism and in photo skin aging. A number of antioxidant enzymes may be induced in response to UV irradiation initially. There is now ample evidence that after UV exposure a rapid cellular antioxidant response is induced, since Cu–Zn-dependent superoxide dismutase (SOD1), manganese-dependent superoxide dismutase (SOD2), glutathione peroxidase and catalase, hemeoxygenase-1 (HO-1), ferritin are induced after solar irradiation in vitro and in vivo.

Superoxide dismutase (SOD) belongs to major antioxidant enzymes that contribute to the homeostasis of oxygen radicals in the skin. It exists in isozymes , cytosolic CuZnSOD and mitochondrial MnSOD. UVA exposure to human dermal fibroblasts in vitro resulted in a significant increase in MnSOD on both mRNA and protein levels. UVB irradiation of human keratinocytes was shown to induce a significant increase in SOD activity and protein level. This increase in SOD was attributed to CuZnSOD. UVB irradiation of the epidermal keratinocytes induced release of IL-1α, IL-1β, and TNF-α that amplified MnSOD activity in dermal fibroblasts. Although the increase of SOD can remove superoxide anion, the product of the reaction – hydrogen peroxide itself can be easily converted to other ROS. The antioxidant enzyme which remove hydrogen peroxide – glutathione peroxidase (GPx) and catalase (CAT) has not been observed to be induced upon UV irradiation. Glutathione peroxidase (GPx) is a selenoprotein, that catalyzes the conversion of UV-induced H2O2 into water and molecular oxygen using GSH as a substrate. The activity is not strongly affected by UV and is considered to be the most important antioxidant defense system in the skin. Catalase (CAT) catalyzes the conversion of H2O2 into water and molecular oxygen thus reduces the damaging effects of H2O2. CAT activity in the skin is strongly reduced after UVA and UVB exposure. Therefore, the overall antioxidant enzyme functionality appear to be reduced by chronic UV exposure.

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