Molecular mechanisms of UV-induced skin responses

Abstract

Ultraviolet radiation (UVR) can profoundly affect human skin as it functionally naked unlike other furred animals. UV-irradiated skin exhibits several unique features, including sunburn and tanning responses at the acute level, an increased risk of developing skin cancer, immunosuppression and photoaging at the chronic level. Among these, tanning (melanogenesis), sunburn and wrinkles are being actively investigated in the clinical and cosmetic fields. The first chapter discusses the molecular mechanism of anti-melanogenic effects of 4-n-butylresorcinol investigated. 4-n-butylresorcinol is a competitive inhibitor of tyrosinase and has been used as an anti-melanogenic agent. However, its anti-melanogenic mechanism(s) in cell is not fully understood. In this study, it was discovered that 4-n-butylresorcinol regulates tyrosinase protein level, but not its mRNA level, through promotion of the proteolytic degradation of tyrosinase. Moreover, 4-n-butylresorcinol-mediated activation of p38 MAPK was observed, which promotes ubiquitination of tyrosinase. Treating B16F10 cells with E64 or proteasome inhibitors restores 4-n-butylresorcinol-mediated decrease of tyrosinase. These findings will assist with the development new, effective and safe agents for the treatment of hyperpigmentation disorders. The second and third chapters discuss the role of transglutaminase 2 (TG2) in UV-irradiated epidermal and dermal tissues investigated. TG2 catalyzes the posttranslational modification of substrate proteins, including crosslinking, polyamination and deamidation. While epidermal keratinocytes and dermal fibroblasts have been known to express TG2, there still is lack of knowledge regarding this enzymes role in regulation of skin homeostasis. Chapter 2 discusses the role of TG2 in UV-induced acute skin inflammation was investigated through the use of human and mouse keratinocytes as well as TG2-deficient mice. TG2-deficient mice exhibited reduced UV-induced skin inflammatory phenotypes, including decreased erythema, edema, dilation of blood vessels, immune cell infiltration and expression of inflammatory cytokines. Using HaCaT cells and primary mouse keratinocytes, it was observed that TG2 is activated following UV irradiation without increase of its protein level and that UV-induced phospholipase C activation followed by ER calcium release was a prerequisite for TG2 activation. Moreover, activated TG2 enhanced transcriptional activity of NF-κB which leads expression of inflammatory cytokine genes such as interleukin-6, -8 and TNF-α. These results not only indicate that TG2 serve as a critical mediator of cytokine expression in the UV-induced inflammatory response of keratinocytes, but also suggest that TG2 inhibition might be a useful target for the prevention of sunburn. Chapter 3 discusses the role of fibroblasts TG2 in UV-exposed fibroblasts investigated by using primary human and mouse dermal fibroblasts and ex vivo mouse skin culture model. In this study, it was revealed that human matrix metalloproteinase (MMP) -1 and -3, and mouse MMP-13 expressions are regulated by UV-induced activation of TG2 as well as its protein level. It was also found that TG2 regulates MMP gene transcription through NF-κB rather than AP-1 pathway. This study provides a new insight that TG2 can be a new therapeutic target for the treatment for UV-induced skin disorders like photoaging. In summary, all of above studies have focused on elucidating molecular mechanisms of responses in UV-irradiated skin cells, including melanocytes, keratinocytes and fibroblasts, and suggest new molecular mechanisms that can be considered in treating of UV-induced skin damages.