Arie A. Vink

Biological consequences of cyclobutane pyrimidine dimers

In the skin many molecules may absorb ultraviolet (UV) radiation upon exposure. In particular, cellular DNA strongly absorbs shorter wavelength solar UV radiation, resulting in various types of DNA damage. Among the DNA photoproducts produced the cyclobutane pyrimidine dimers (CPDs) are predominant. Although these lesions are efficiently repaired in the skin, this CPD formation results in various acute effects (erythema, inflammatory responses), transient effects (suppression of immune function), and chronic effects (mutation induction and skin cancer). The relationships between the presence of CPD in skin cells and the subsequent biological consequences are the subject of the present review.

Attenuation of biologically effective UV radiation in tropical atlantic waters measured with a biochemical DNA dosimeter

Abstract— A biochemical dosimeter was developed to study the attenuation of biologically effective UV radiation in marine tropical waters. Small quartz vials were used containing a solution of DNA molecules; the vials were incubated at discrete water depths. Subsequently, DNA damage was determined in these samples, using an antibody directed against thymine dimers followed by chemiluminescent detection. Measurements of DNA damage were compared with calculated biologically effective doses, as derived from spectroradiometer measurements. The biodosimeter was found to be a reliable and easy tool to determine levels of harmful UV radiation in marine waters. The highest attenuation coefficient (1.60 m‐l) measured with the biochemical dosimeter was found in eutrophic waters, at a coastal station off Curabcao, Netherlands Antilles. At the other stations attenuation coefficients ranged from 0.18 m‐1 in central Atlantic waters to 0.43 m‐1 close to the Curapcao coast line. Latter results indicate that biologically effective UV radiation may easily reach ecologically significant depths, e.g. coral reef communities.

Removal of UV-induced DNA lesions in mouse epidermis soon after irradiation

Induction and removal of cyclobutane thymine dimers and (6-4)photoproducts were studied in epidermal DNA isolated from UV-exposed hairless mice. For the detection of DNA damage, lesion-specific monoclonal antibodies were used in an immunoslotblot assay. Following the exposure of mice to 3.0 kJ m-2 UV-B, substantial removal of both thymine dimers (66%) and (6-4)photoproducts (77%) was observed at 24 h after irradiation. No removal, however, was detected at 4 h after irradiation. In contrast, immunofluorescence data obtained previously showed a rapid initial dimer removal after irradiation with 1.0 kJ m-2 UV-B (A.A. Vink, R.J.W. Berg, F.R. De Gruijl, L. Roza and R.A. Baan, Carcinogenesis, 12 (1991) 861-864). Reinvestigation of the removal of dimers and (6-4)-photoproducts shortly after three different UV doses showed a rapid decreases of both lesions at 2 h after irradiation with 1.0 kJ m-2. The results obtained after irradiations with 2.0 and 3.0 kJ m-2 UV-B suggest a saturation of repair already at 2.0 kJ m-2. Cyclobutane dimers were found to be removed at a lower rate than (6-4)photoproducts.

Rôle of DNA damage in local suppression of contact hypersensitivity in mice by UV radiation

Abstract Exposure of mice to UVB radiation down‐regulates the induction of contact hypersensitivity (CHS) responses to haptens applied to the site of irradiation. Concomittantly, the activity of antigen‐presenting cells (APC) in the draining lymph nodes is decreased, and T lymphocytes that suppress the induction of CHS are induced. We assessed the röle of DNA damage in modulation of the CHS response by UV irradiation by applying liposomes containing T4 endonuclease V (T4N5) to the UV‐irradiated skin. Liposomal T4N5. which increases the rate of repair of cyclobutyl pyrimidine dimers (CPD) in DNA. prevented the reduction in the CHS response, the impairment in APC function, and the induction of transferrable immune suppression. Liposomes containing heat‐inactivated T4N5 did not restore immune responsiveness. In this model, hapten‐bearing APC from unirradiated mice also fail to induce CHS upon injection into UV‐irradiated recipients. This systemic effect of UV irradiation on APC function was also prevented by application of liposomes containing active, but not inactive, T4N5. These studies support the hypothesis that DNA damage is an essential initiator of one or more steps leading to impaired immune responsiveness after UV irradiation. They further imply that the release of cytokines that modulate APC function after UV irradiation is triggered by DNA damage.

Cellular target of UVB-induced DNA damage resulting in local suppression of contact hypersensitivity

Experimental data are reviewed that lend support to the hypothesis that formation of DNA damage is the initiation event of local suppression of contact hypersensitivity (CHS) after exposure to ultraviolet (UV) radiation and that the antigen-presenting cell (APC) is an important target for this DNA damage.

Inhibition of intercellular adhesion molecule-1 (ICAM-1) expression in ultraviolet B-irradiated human antigen-presenting cells is restored after repair of cyclobutane pyrimidine dimers

Abstract: The present study assessed the molecular mechanism underlying ultraviolet (UV) B radiation‐induced inhibition of the expression of the adhesion molecule ICAM‐1 in human antigen‐presenting cells (APC). UVB radiation‐induced inhibition of ICAM‐1 expression in human peripheral blood monocytes was associated with the generation of cyclobutane pyrimidine dimers (CPD). CPD were reduced by 60% after treatment with liposomal packed photolyase, an enzyme which removes CPD after absorption of photoreactivating light. Although incomplete, reduction of CPD was associated with complete restoration of ICAM‐1 expression at the mRNA and protein level. Neither reduction of CPD level nor restoration of ICAM‐1 expression were observed, if monocytes were treated with empty liposomes, or if they were irradiated with photoreactivating light prior to application of photolyase. DNA damage might also induce soluble mediators capable of autocrine inhibition of ICAM‐1 expression. UVB irradiation of monocytes did not induce IL‐10 production, but resulted in release of prostaglandin (PG) E2. Treatment of unirradiated monocytes with PGE2 completely inhibited ICAM‐1 expression, thus mimicking the UVB effect. Inhibition of monocytic PGE2 production by indomethacin, however, did not restore ICAM‐1 expression. These results suggest that formation of CPD is necessary and sufficient for UVB radiation‐induced inhibition of ICAM‐1 expression. In contrast, PGE2 might serve a paracrine role in UVB radiation‐induced immunosuppression.

The mechanism of N-acetylcysteine photoprotection is not related to dipyrimidine photoproducts

Topical application of N-acetylcysteine prior to UVB irradiation of BALB/c mice has previously been shown to inhibit systemic suppression of the contact hypersensitivity response. Formation of cis-urocanic acid, however, is not affected. Besides urocanic acid, UV-induced DNA damage has been held responsible for the initiation of suppression of the contact hypersensitivity response. Therefore, the possible inhibitory effect of N-acetylcysteine on UVB-induced cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts has been investigated. No effect on the photoproducts studied is observed, suggesting that N-acetylcysteine exerts its photoprotective effect during the post-initiation phase of photoimmunosuppression.