Carvedilol Prevents UV-Induced Immunosuppression and Skin Carcinogenesis through a Mechanism Independent of β-Blockade

Abstract

Exposure to UVR suppresses the immune system, which plays a primary role in skin cancer etiology. The β-blocker carvedilol prevents UV-induced skin cancer, but the mechanism is unknown. This study examined the effects of carvedilol and its enantiomers on UV-induced immunosuppression using contact hypersensitivity (CHS) response in SKH-1 mice. A single-dose UVR (224 mJ/cm²) strongly suppressed CHS, which was attenuated by intraperitoneal injection of carvedilol before UV exposure. Adoptive transfer of lymphocytes isolated from UV-irradiated mice to naïve mice without UV exposure triggered CHS suppression, which was not observed for lymphocytes isolated from carvedilol-treated mice. Topically applied carvedilol also prevented UV-induced CHS suppression. Both the β-blocking S-carvedilol and non–β-blocking R-carvedilol attenuated UV-induced CHS suppression. To evaluate the role of β2-adrenergic receptor, a knockout mouse model of β2-adrenergic receptor on the SKH-1 background was used. UV suppressed CHS in β2-adrenergic receptor–knockout mice, and carvedilol attenuated UV-induced CHS suppression in both genotypes. Furthermore, wild-type and knockout mice exposed to chronic UVR developed skin tumors with similar incidence, multiplicity, and tumor burden, whereas carvedilol inhibited skin tumor development in both genotypes. These data suggest that carvedilol prevents skin cancer not through β-blocking but through its activity overcoming UV-induced immunosuppression.