Differential Role of Basal Keratinocytes in UV-Induced Immunosuppression and Skin Cancer

Abstract

Cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) comprise major UV-induced photolesions. If left unrepaired, these lesions can induce mutations and skin cancer, which is facilitated by UV-induced immunosuppression. Yet the contribution of lesion and cell type specificity to the harmful biological effects of UV exposure remains currently unclear. Using a series of photolyase-transgenic mice to ubiquitously remove either CPDs or 6-4PPs from all cells in the mouse skin or selectively from basal keratinocytes, we show that the majority of UV-induced acute effects to require the presence of CPDs in basal keratinocytes in the mouse skin. At the fundamental level of gene expression, CPDs induce the expression of genes associated with repair and recombinational processing of DNA damage, as well as apoptosis and a response to stress. At the organismal level, photolyase-mediated removal of CPDs, but not 6-4PPs, from the genome of only basal keratinocytes substantially diminishes the incidence of skin tumors; however, it does not affect the UVB-mediated immunosuppression. Taken together, these findings reveal a differential role of basal keratinocytes in these processes, providing novel insights into the skin's acute and chronic responses to UV in a lesion-and cell-type-specific manner.Exposure to UV light has undesired health consequences with increasing impact; apart from acute effects (e.g., sunburn), skin tumors are considered a major threat, demonstrated by their increasing incidence in white populations, due to altered life style and the erosion of the protecting ozone layer (1, 43). Besides the ability of RNA (20, 21) and proteins (5) to absorb light at the UV wavelength, our recent findings have unequivocally pointed to DNA as the biologically most relevant target of UV radiation (12,22,35). UV induces the formation of major dimer configurations, namely the cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs), generated by covalent bonds between two adjacent pyrimidines, that interfere with biological processes (e.g., transcription and replication) critical for cell viability (28).To recognize and remove effectively the wide range of hazardous DNA lesions, mammalian cells employ a resourceful battery of DNA repair systems (10,

Induction of neoplastic cells in rat skin

“…One can infer from this study that UVR-B seems to induce its harmful effects on the skin cells by causing acute inflammatory reaction with the expressive presentation of erythema in three times and although, in general, the inflammatory response constitutes an organic process very important defensive for numerous physiological events, in many cases the persistent inflammatory reaction can cause irreversible cell damage, contributing to photoaging 3,21 .…”

“…The initial lesion (erythema) suggests that the body reacts to UVR-B with the same process of an initial inflammatory reaction, or the dissemination of inflammatory mediators, such as cytokines released from harmed keratinocytes, associated with the fact that the UVR-B can depress the immune response of the skin 3,4,20 .…”

“…For each new exhibition there are major changes. Photobiological effects over time can be observed on the skin, immediately or later [3][4][5] .…”

UV-Induced Immune Suppression that Promotes Skin Cancer Development and Progression

“…Using mouse models, the additional factors that influence the NER and reverse UV-induced immunosuppression have been demonstrated, including IL-18 , IL-23 (Majewski et al), α-melanocyte-stimulating hormone (Bohm et al, 2005), infrared radiation (Jantschitsch et al, 2009), vitamin D (Tremezaygues et al, 2009, and even UV-A (Garssen et al, 2001) possibly through the induction of IL-12 (Shen et al, 1999); however, their relevance in human subjects remains to be determined. Although UV radiation induces different types of DNA lesions such as CPDs and 6-4PPs along with its isomeric secondary product, Dewar valence isomer, it was later found that repair of 6-4PPs had no effect on UV-induced immunosuppression (Jans et al, 2006). Using mice expressing the P. tridacylus CPD photolylase enzyme under the control of the basal keratinocyte-specific promoter keratin-14, which allows rapid, light-dependent removal of CPDs from basal keratinocytes only, it was demonstrated that removal of CPDs solely from basal epidermal cells in transgenic mice resulted in a major reduction in UV-induced carcinogenesis, but did not reverse UV-induced immunosuppression, whereas the removal from the entire skin reversed UV-induced immunosuppression (Jans et al, 2006).…”

“…These photolesions are highly mutagenic because of error-prone repair that results in thymidine substitutions. Although the contribution of 6-4PPs to UV-induced carcinogenesis has been elusive (Jans et al, 2006), the causative role of CPDs in UV-induced carcinogenesis was substantiated by specific removal of these DNA lesions through DNA repair enzymes leading to significantly reduced risk of UV-induced skin cancer in mice (Jans et al, 2005) and human Yarosh et al, 2001). Besides the formation of DNA-lesions, cis-urocanic acid (cis-UCA) is formed from its isomer trans-UCA, which is abundant in skin exposed to UV radiation.…”