Silibinin inhibits ultraviolet B radiation-induced DNA-damage and apoptosis by enhancing interleukin-12 expression in JB6 cells and SKH-1 hairless mouse skin.
Recent studies have demonstrated silibinin efficacy against ultraviolet B (UVB)-induced skin carcinogenesis via different mechanisms in cell lines and animal models; however, its role in regulating interleukin-12 (IL-12), an immunomodulatory cytokine that reduces UVB-induced DNA damage and apoptosis, is not known. Here, we report that UVB irradiation causes caspase 3 and PARP cleavage and apoptosis, and addition of recombinant IL-12 or silibinin immediately after UVB significantly protects UVB-induced apoptosis in JB6 cells. IL-12 antibody-mediated blocking of IL-12 activity compromised the protective effects of both IL-12 and silibinin. Both silibinin and IL-12 also accelerated the repair of UVB-caused cyclobutane-pyrimidine dimers (CPDs) in JB6 cells. Additional studies confirmed that indeed silibinin causes a significant increase in IL-12 levels in UVB-irradiated JB6 cells as well as in mouse skin epidermis, and that similar to cell-culture findings, silibinin topical application immediately after UVB exposure causes a strong protection against UVB-induced TUNEL positive cells in epidermis possibly through a significantly accelerated repair of UVB-caused CPDs. Together, these findings for the first time provide an important insight regarding the pharmacological mechanism wherein silibinin induces endogenous IL-12 in its efficacy against UVB-caused skin damages. In view of the fact that an enhanced endogenous IL-12 level could effectively remove UVB-caused DNA damage and associated skin cancer, our findings suggest that the use of silibinin in UVB-damaged human skin would also be a practical and translational strategy to manage solar radiation-caused skin damages as well as skin cancer.
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado.
Sreekanth
S
Narayanapillai
Chapla
C
Agarwal
Gagan
G
Deep
Rajesh
R
Agarwal
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects*; D004260:DNA Repair / Q000187:drug effects; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D018664:Interleukin-12 / Q000235:genetics* / Q000494:pharmacology; D051379:Mice; D011837:Radiation-Protective Agents / Q000494:pharmacology; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects*
D011837:Radiation-Protective Agents; D012838:Silymarin; D018664:Interleukin-12; D000077385:Silybin
DNA damage and repair; apoptosis; cyclobutane-pyrimidine dimers; non-melanoma skin cancer; silibinin