Silymarin inhibits UV radiation-induced immunosuppression through augmentation of interleukin-12 in mice

Abstract

We have shown previously that silymarin, a plant flavonoid, inhibits UVB-induced photocarcinogenesis in mice. As UVB-induced immunosuppression has been implicated in the development of skin cancer, we investigated whether silymarin can modulate the effects of UVB radiation on the immune system. Treatment of C3H/HeN mice with topically applied silymarin (0.5 or 1.0 mg/cm 2 ) or silibinin, a major component of silymarin, markedly inhibited UVB (180 mJ/cm 2 ) -induced suppression of contact hypersensitivity response in a local model of immunosuppression and had a moderate inhibitory effect in a systemic model of contact hypersensitivity. Silymarin reduced the UVB-induced enhancement of the levels of the immunosuppressive cytokine, interleukin (IL)-10, in the skin and draining lymph nodes and enhanced the levels of the immunostimulatory cytokine, IL-12. Intraperitoneal injection of mice treated with silymarin with an endotoxin-free neutralizing anti-IL-12 antibody abrogated the protective effects of the silymarin against UVB-induced suppression of the contact hypersensitivity response. Furthermore, the treatment of silymarin did not prevent UVB-induced suppression of the contact hypersensitivity response in IL-12 knockout mice but prevented it in their wild-type mice. Moreover, i.p. injection of IL-12 to silymarin-treated or nonsilymarin-treated IL-12 knockout mice resulted in an enhanced response to contact hypersensitivity compared with the response in mice that were exposed to either UVB alone or silymarin plus UVB. These data indicate for the first time that silymarin has the ability to protect mice from UVB-induced immunosuppression and that this protective effect is mediated, at least in part, through

Topical delivery of silymarin constituents via the skin route

“…Exposure of skin to ultraviolet (UV) radiation results in a variety of biological effects, including inflammation, induction of oxidative stress, formation of sunburned cells, and immunologic alterations [1] . All of these play important roles in the development of non-melanoma skin cancer (NMSC), which is the most frequently diagnosed malignancy in Caucasians around the world [2,3] .…”

“…Both UVA and UVB cause wavelength-dependent damage to human skin including skin cancer, whose incidence is dramatically increasing [8] . Recent studies showed that silymarin constituents could strongly protect against photocarcinogenesis and inhibit UVB and chemical tumor promoterinduced skin inflammation and edema [1,[9][10][11] . Silymarin also attenuates UVA-induced damage to human keratinocytes [12] .…”

Interleukin-12 and photocarcinogenesis

“…In chemoprevention studies, it has been shown that dietary feeding of grape seed proanthocyanidins inhibit UVB-induced immunosuppression, and the inhibition of immunosuppression by grape seed proanthocyanidins was associated with the induction of IL-12 in mice (Sharma and Katiyar, 2006). Similarly, it was also found that topical treatment of mice with silymarin, a plant flavonoid, inhibits UVB-induced immunosuppression through augmentation of IL-12 in the skin and draining lymph nodes (Meeran et al, 2006). These observations support the notion that IL-12 has a significant preventive role in UV radiationinduced immune suppression.…”

“…Recently, we and others have reported that IL-12 exhibits the capacity to remove or repair UV-induced DNA damage, and that the prevention of UV radiation-induced immunosuppression by IL-12 is dependent on DNA repair. This repair of damaged DNA by IL-12 is mediated through nucleotide excision repair mechanism (Schwarz et al, 2002;Meeran et al, 2006). If the DNA damage is irreparable, the keratinocyte cell cycle is arrested and it is transformed into a sunburn cell, an initial morphological indicator of epidermal cell apoptosis.…”

Photoprotection of natural flavonoids

“…The treatment also resulted in significant reduction of UVB-induced immunosuppressive cytokine interleukin-10 producing cells and its production (Katiyar et al, 1997;Katiyar, 2002). Silymarin inhibits photocarcinogenesis through inhibition of UVB-induced oxidative stress, inflammation and suppression of immune system (Katiyar, 2005;Katiyar et al, 2008;Meeran et al, 2006). It has the ability to decrease UV radiation-induced apoptotic cell death of epidermal cells through repair of damaged DNA and thus lead to prevention of photocarcinogenesis.…”