DNA DOUBLE-STRAND BREAKS IN EPIDERMAL-CELLS CAUSE IMMUNE SUPPRESSION IN-VIVO AND CYTOKINE PRODUCTION IN-VITRO

UV irradiation of the skin causes immune suppression by a mechanism in volving epidermal cytokines. To determine the role of epidermal DNA da mage in immune suppression, we used HindIII restriction endonuclease e ncapsulated in liposomes to cause DNA strand breaks in epidermal cells in vivo and in vitro. Topical application of HindIII in liposomes to murine skin in vive impaired the induction of contact hypersensitivity responses initiated either locally or at distant sites and impaired t he function of APCs. Unlike UV-B radiation, however, treatment of mice with HindIII in liposomes before contact sensitization did not induce tolerance or transferable suppression. The liposome-encapsulated Hind III caused double strand breaks in DNA and induced IL-10 and TNF-alpha production when added to cells of a murine keratinocyte line in vitro . Topical application of liposomal HindIII also induced TNF-alpha in t he epidermis of mice. Liposomes containing heat-inactivated HindIII or an endonuclease specific for pyrimidine dimers in DNA did not exhibit these effects. These results support the hypothesis that DNA damage i s a trigger for the production of cytokines that modulate immune respo nses. They also suggest that immune suppression and suppressor cell in duction are separate consequences of cutaneous injury that require dif ferent stimuli.