Evidence that DNA damage is a mediate in ultraviolet B radiation-induced inhibition of human gene expression: ultraviolet B radiation effects on intercellular adhesion molecule-1 (ICAM-1) expression.
Expression of intercellular adhesion molecule-1 (ICAM-1) is a prerequisite for the capacity of cells to physically interact with leukocytes. Ultraviolet B radiation previously was found to inhibit interferon gamma-induced ICAM-1 expression in human keratinocytes by suppressing interferon gamma-mediated upregulation of ICAM-1 mRNA levels. Because ultraviolet B radiation induces photoproducts in cellular DNA, the potential role of ultraviolet B radiation-induced DNA damage in this system was assessed. For this purpose, cells from a normal donor were compared with cells from patients with xeroderma pigmentosum from complementation groups C and D. Xeroderma pigmentosum cells are defective in the removal of ultraviolet B radiation-induced DNA lesions, and thus lower ultraviolet B radiation doses are required to retain equivalent numbers of DNA photoproducts at a given time point after irradiation. In the present study, ultraviolet B radiation inhibited interferon gamma-induced ICAM-1 mRNA expression in primary human skin fibroblasts in a manner identical to that previously observed for keratinocytes. Comparative studies employing normal versus xeroderma pigmentosum fibroblasts revealed that in xeroderma pigmentosum fibroblasts, two- to threefold lower ultraviolet B radiation doses were required to achieve inhibition equivalent to that observed in normal fibroblasts. In irradiated normal cells, inhibition of interferon gamma-induced ICAM-1 mRNA expression was transient and restored 12 h after ultraviolet B radiation exposure. In contrast, in xeroderma pigmentosum complementation group D cells, no restoration could be observed for up to 48 h, but responsiveness was restored in xeroderma pigmentosum complementation group C cells after 24 h. These studies indicate that ultraviolet B radiation-induced inhibition of interferon gamma-mediated ICAM-1 expression involves the generation of DNA photo-products.
Krutmann
J
J
Department of Dermatology, University of Freiburg, Germany.
Bohnert
E
E
Jung
E G
EG
D015815:Cell Adhesion Molecules / Q000235:genetics*; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000187:drug effects / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000528:radiation effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D014466:Ultraviolet Rays
D015815:Cell Adhesion Molecules; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma