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Evidence that DNA damage is a mediate in ultraviolet B radiation-induced inhibition of human gene expression:
J Krutmann1, E Bohnert, E G Jung
1Department of Dermatology, University of Freiburg, Germany.
Abstract:
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.
Insights
Ultraviolet B radiation inhibits interferon gamma-induced ICAM-1 expression by damaging DNA. This inhibition is linked to DNA photoproducts, with impaired DNA repair in xeroderma pigmentosum cells prolonging the effect.
Area of Science:
- Dermatology
- Molecular Biology
- Immunology
Background:
- Intercellular adhesion molecule-1 (ICAM-1) expression is crucial for leukocyte interaction.
- Ultraviolet B (UVB) radiation inhibits interferon gamma (IFN-γ)-induced ICAM-1 expression in keratinocytes by suppressing mRNA levels.
Purpose of the Study:
- To investigate the role of UVB-induced DNA damage in the inhibition of IFN-γ-mediated ICAM-1 expression.
- To compare the effects of UVB on ICAM-1 expression in normal cells versus cells with defects in DNA repair.
Main Methods:
- Comparing primary human skin fibroblasts from normal donors and patients with xeroderma pigmentosum (XP) complementation groups C and D.
- Assessing UVB-induced inhibition of IFN-γ-mediated ICAM-1 mRNA expression and its recovery over time post-irradiation.
Main Results:
- UVB inhibited IFN-γ-induced ICAM-1 mRNA expression in normal fibroblasts, similar to keratinocytes.
- Lower UVB doses were required to achieve equivalent inhibition in XP fibroblasts compared to normal fibroblasts.
- Inhibition was transient in normal cells (restored by 12h), but prolonged in XP group D cells (no restoration up to 48h) and partially restored in XP group C cells (by 24h).
Conclusions:
- UVB-induced inhibition of IFN-γ-mediated ICAM-1 expression is mediated by the generation of DNA photoproducts.
- Efficient DNA repair is essential for the transient nature of UVB's inhibitory effect on ICAM-1 expression.