Intracellular Mechanisms Involved in UVInduced Immunosuppression

Several candidate molecules have been proposed as the cellular photoreceptors for UVB irradiation whereby nuclear DNA is considered the major UVB-absorbing chro-mophore (Applegate et al. 1989,Gordon andHaseltine 1982,Tan and Stoughton 1969). UVB irradiation has been found to primarily induce two types of photolesions in DNA, cyclobutane pyrimidine dimers and 6-4-photoproducts (Freeman et al. 1986, 1989, Ley et al. 1991, Mitchell and Nairn 1989, Yarosh et al. 1994). For many years, it has been proposed that UVB-induced DNA damage plays an essential role in UVB-induced immunosuppression, since the formation of DNA photoproducts by UV light is associated with various cellular responses, including the activation of many genes.

Data to support this hypothesis stems from the marsupial model Monodelphis domestica (Ley et al. 1991). In contrast to humans, UVB-induced DNA lesions in this animal are excised via a repair process called photoreactivation. As a result, DNA damage is removed more rapidly when these animals are exposed to visible light after UVB irradiation. Correspondingly, exposing these animals to visible light immediately after UVB irradiation significantly reduced the UVB-mediated inhibition of CHS responses. Because this photoreactivation removes DNA lesions, the inference was made that UVB-induced DNA damage is critically involved in signaling processes elicited by UVB-induced damage and the ensuing immunosuppression.

This hypothesis was further supported by studies using the DNA excision repair enzyme T4 endonuclease V (T4N5), which increases the rate of repair of UV-induced DNA damage in human cells (Yarosh et al. 1984). Topical application of T4N5 incorporated into a liposomal delivery system to the UVB-damaged skin prevented UV-induced impairment of the CHS response (Kripke et al. 1992). Further supporting data were provided by studies in which the release of the cytokines IL-10 and TNF-a triggered by UV irradiation of keratinocytes was considerably suppressed after treatment with T4N5 (Kibitel et al. 1991, Nishigori et al. 1996). Further evidence was made available by studies conducted in a mouse model in which essential components of the nucleotide excision repair system, the endogenous repair system, were knocked out (Boonstra et al. 2001). These animals are more susceptible to UV-induced immunosuppression, and these studies underlined that both global and transcription-coupled repair are needed to mitigate immunomodulation by UVB. The substantial role of DNA damage in the processes involved in UVB-induced immunosup-pression was recently also confirmed in humans in vivo. In research conducted by Stege et al., nickel was used as a model contact sensitizer, and volunteers who were hypersensitive to nickel were treated with a placebo or the DNA repair enzyme pho-tolyase immediately after UVB exposure (Stege et al. 2000). Nickel-specific hypersen-sitivity reactions were prevented after photolyase treatment, once again supporting the role of DNA damage as an essential factor involved in impaired immune responsiveness after UV irradiation.

Recent published studies documented a potential connection between DNA damage and IL-12 (Schmitt et al. 2000, Schwarz et al. 2002). IL-12 was able to reduce cyclobutane pyrimidine dimers in both mice and humans, and the reduction of UVB-induced damage seemed to depend on nucleotide excision repair, since this unique effect was not observed in knockout mice in which the nucleotide excision repair was defective. Because DNA damage is a key factor in the modulation of the immunosuppressive effects elicited by UVB radiation and IL-12 alleviates UVB-induced immuno-suppression, it is tempting to speculate whether at least part of the immunoreconsti-tutive effects of IL-12 originate from its ability to decrease DNA damage. The observation that IL-12 inhibits UVB-induced IL-10 release, which is mediated via DNA damage, gives further support to this speculation (Nishigori et al. 1996, Schmitt et al. 2000). On the other hand, one should not forget the evidence of extranuclear cellular UVB targets involved in photoimmunology. UVB radiation effects the release of many cytokines, which can modulate immune responses and may also interfere with the biological activities of immune mediators, whether they be depletion or alteration of the functionality of antigen-presenting or T cells. For example, UVB irradiation interferes with the signal transduction pathway of interferon-y and IL-2, both important immunomodulatory cytokines (Aragane et al. 1997, Kulms and Schwarz 2001). An alternative means by which UVB irradiation could have an effect is by inhibiting the phosphorylation of important signal transduction proteins involved in the signaling of these two cytokines.

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