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4-Aminoquinoline antimalarials enhance UV-B induced c-jun transcriptional activation
T Q Nguyen1, J D Capra, R D Sontheimer
1Department of Dermatology, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Abstract:
Previous work has documented that the earliest observable response in mammalian cells following ultraviolet (UV) irradiation is the activation of plasma membrane-associated Src tyrosine kinases. These molecules then trigger a signalling cascade that results in activation of the transcription factor AP-1 which subsequently transactivates the early immediate genes including c-jun. This pathway has been postulated to play a protective role against UV damage. As aminoquinoline antimalarials such as chloroquine are known to downregulate several photoinduced cutaneous disorders including LE-specific skin disease, we asked whether chloroquine might be capable of modulating this early limb of the UV light response. A431 cells (a human epidermal keratinocyte cell line) that had been transfected with a c-jun luciferase reporter gene construct were then treated with physiologically relevant concentrations of chloroquine followed by exposure to 0-125 J/m2 of UV-B from a bank of unfiltered FS20 lamps. Chloroquine pretreatment resulted in a dose-dependent increase in luciferase activity in permanently transfected A431 cells (luciferase activity was increased by 45% at 2.5 x 10(-5) M chloroquine and 125 J/m2 of UV-B). Hydroxychloroquine pretreatment also resulted in an increase in luciferase activity. Primaquine, an 8-aminoquinoline, did not influence the UV-B induced c-jun activity. Furthermore, chloroquine did not have a similar impact on HSP-70 gene activity during heat shock. These studies suggest that the beneficial effect of the 4-aminoquinoline antimalarials in various photodermatoses including cutaneous LE might result in part from the capacity of these drugs to enhance the protective early limb of the UV response.
Insights
Chloroquine enhances the UV-B response pathway involving c-jun transcription factor in skin cells. This suggests 4-aminoquinoline antimalarials may protect against photodermatoses by boosting UV protection mechanisms.
Area of Science:
- Cellular and Molecular Biology
- Photobiology
- Dermatology
Background:
- Ultraviolet (UV) irradiation activates Src tyrosine kinases, initiating a signaling cascade that leads to AP-1 activation and c-jun gene expression.
- This UV-induced pathway is believed to offer cellular protection against DNA damage.
- Aminoquinoline antimalarials, like chloroquine, are known to mitigate photoinduced skin conditions, including lupus erythematosus (LE).
Purpose of the Study:
- To investigate whether chloroquine can modulate the early signaling pathway activated by UV light.
- To determine if chloroquine affects the UV-B induced activation of the c-jun gene.
Main Methods:
- A431 human epidermal keratinocyte cells were transfected with a c-jun luciferase reporter gene.
- Cells were pretreated with varying concentrations of chloroquine before exposure to UV-B radiation.
- Luciferase activity was measured to quantify c-jun gene activation. HSP-70 gene activity was also assessed under heat shock conditions.
Main Results:
- Chloroquine pretreatment dose-dependently increased UV-B induced luciferase activity, indicating enhanced c-jun activation.
- Hydroxychloroquine also increased luciferase activity, while primaquine did not affect UV-B induced c-jun activity.
- Chloroquine did not impact heat shock-induced HSP-70 gene activity, suggesting a specific effect on the UV response pathway.
Conclusions:
- 4-aminoquinoline antimalarials, such as chloroquine, may exert beneficial effects in photodermatoses partly by enhancing the protective early UV response pathway.
- The findings suggest a potential therapeutic mechanism for chloroquine in managing UV-related skin disorders.