Pyrimidine dimers in DNA initiate systemic immunosuppression in UV-irradiated mice.

Abstract

Exposing the skin of mice to UV radiation interferes with the induction of delayed and contact hypersensitivity immune responses initiated at nonirradiated sites. The identity of the molecular target in the skin for these Immunosuppressive effects of UV radiation remains controversial. To test the hypothesis that DNA is the target for UV-induced systemic immunosuppression, we exposed C3H mice to UV radiation and then used liposomes to deliver a dimer-specific excision repair enzyme into the epidermis in situ. The application of T4 endonuclease V enulated in liposomes to UV-irradiated mouse skin decreased the number of cyclobutane pyrimidine dimers in the epidermis and prevented suppression of both delayed and contact hypersensitivity responses. Moreover, the formation of suppressor lymphoid cells was inhibited. Control, heat-inactivated endonuclease encapsulated in liposomes had no effect. These studies demonstrate that DNA is the major target of UV radiation in the generation of systemic immunosuppression and suggest that the primary molecular event mediating these types of immunosuppression by UV radiation is the formation of pyrimidine dimers. Furthermore, they illustrate that the delivery of lesion-specific DNA repair enzymes to living skin after UV Irradiation is an effective tool for restoring Immune function and suggest that this approach may be broadly applicable to preventing other alterations caused by DNA damage.Wavelengths of UV radiation in the middle, or UV-B (280-320 nm), range can impair a variety of immune responses in humans and laboratory animals both locally, within UVirradiated skin, and systemically, at distant sites (1). Exposure of mice to UV-B radiation interferes with the rejection of UV-induced skin cancers and the induction of delayed and contact hypersensitivity (DHS and CHS) responses initiated at unirradiated sites; these forms of immune suppression are associated with the induction of antigen-specific suppressor T lymphocytes (2). How UV-B radiation exerts its systemic, immunosuppressive effects is a question of considerable interest, both for understanding the regulatory pathways governing these immune responses and for assessing the potential effects of UV-B radiation on human health. The DHS response is particularly important in this regard because this T-lymphocyte-mediated immune reaction is responsible for protection against many chronic infectious diseases.Current experimental evidence implicates soluble substances derived from UV-irradiated keratinocytes as the probable mediators of UV-induced systemic suppression of DHS and CHS responses (3-5). However, the initial photobiological reaction responsible for triggering the cascade of events leading to activation of the suppressor pathway of the immune response remains controversial. Based on an in vivo action spectrum for systemic suppression of CHS in the mouse, it has been proposed that urocanic acid, a deamination product of histidine, present in the stratum corneum, is the photoreceptor for this form of UV-induce...

Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

“…Exposure to systemic low-dose solarstimulated UV containing 140 mJ/cm 2 UVB generated activated B cells in sDLNs, which were able to inhibit dendritic cells from stimulating T-cell-mediated skin immune reactions. 29 Pioneering work by Kripke et al 19 demonstrated that CPD formation and transferable suppressor cells are responsible for DTH suppression by systemic UVB, which is unlike this study. Notably, our investigation differed in the Ag and source of UV used.…”

“…Control mice received 125 ng of empty liposomes. 19 Transfer of Regulatory CD4 ϩ CD25 ϩ T Cells Mice were irradiated with 150 mJ/cm 2 UVB daily for 3 days and immunized with ova 3 days after the last UVB irradiation; 7 days after immunization, the sDLNs (brachial, axillary, and inguinal) were removed. Cells from unirradiated but immunized mice were also harvested.…”

“…The use of liposomes containing T4N5, which initiates repair of CPD, has prevented systemic UVB-induced suppression of a DTH to fungal Ag. 19 Therefore, immediately after each irradiation, mice were topically administered T4N5 liposomes. However, we found that T4N5 liposomes did not rescue mice from the inhibitory effects of this low-dose UVB on CD8 T-cell activation.…”

The dark side of the light: mechanisms of photocarcinogenesis

“…23,29,32,33,35 Topically applied exogenous DNA repair enzymes can prevent the immune system suppression induced by UVR. 36 UVR also affects cytoplasmic and membrane targets acting as additional photoreceptors for UVR-induced immunosuppression. 33 Trans-urocanic acid (UCA), present in large amounts in the stratum corneum, is an epidermal chromophore that undergoes photoisomerization to its cis-UCA conformation upon UV exposure; cis-UCA, whose receptor is 5-HT 2A , is involved in skin photocarcinogenesis by acting as a mediator of UV-induced immunosuppression.…”

Interleukin-12 and photocarcinogenesis

“…UV-induced DNA damage, predominantly in the form of cyclobutane pyrimidine dimers (CPDs) or thymine dimers, has been recognized as an important molecular trigger for the suppression of immune responses (Applegate et al, 1989) and initiation of UV-carcinogenesis (Applegate et al, 1989;Kripke et al, 1992;Yarosh et al, 1992). In turn, accelerated or enhanced removal of UV-induced CPDs through the topical application of the bacterial DNA repair enzyme, T4 endonuclease V, impaired the development of skin tumors in mice exposed to chronic UV radiation .…”