Prevention of Ultraviolet Radiation–Induced Immunosuppression by (−)-Epigallocatechin-3-Gallate in Mice Is Mediated through Interleukin 12–Dependent DNA Repair

• Published in: Clinical cancer research 2006-04, Vol.12 (7), p.2272-2280
• Main Authors: MEERAN, Syed M, MANTENA, Sudheer K, KATIYAR, Santosh K
• Format: Article
• Language: English
• Subjects: Administration, Topical; Animals; Anticarcinogenic Agents - administration & dosage; Anticarcinogenic Agents - pharmacology; Antineoplastic agents; Biological and medical sciences; Catechin - administration & dosage; Catechin - analogs & derivatives; Catechin - pharmacology; Cells, Cultured; Contact hypersensitivity; cyclobutane pyrimidine dimer; DNA repair; DNA Repair - radiation effects; Genotype; Humans; Immune System - drug effects; Immune System - radiation effects; Immune Tolerance - drug effects; Immune Tolerance - immunology; Immune Tolerance - radiation effects; interleukin-12; Interleukin-12 - deficiency; Interleukin-12 - genetics; Interleukin-12 - radiation effects; Medical sciences; Mice; Mice, Inbred C3H; Mice, Knockout; Pharmacology. Drug treatments; Sensitivity and Specificity; Ultraviolet Rays - adverse effects; UV radiation
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-2672

Purpose: Solar UV radiation–induced immunosuppression is considered to be a risk factor for melanoma and nonmelanoma skin cancers. We previously have shown that topical application of (−)-epigallocatechin-3-gallate (EGCG) prevents UV-induced immunosuppression in mice. We studied whether prevention of UV-induced immunosuppression by EGCG is mediated through interleukin 12 (IL-12)–dependent DNA repair. Experimental Design: IL-12 knockout (KO) mice on C3H/HeN background and DNA repair–deficient cells from xeroderma pigmentosum complementation group A ( XPA ) patients were used in this study. The effect of EGCG was determined on UV-induced suppression of contact hypersensitivity and UV-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPD) in mice and XPA -deficient cells using immunohistochemistry and dot-blot analysis. Results: Topical treatment with EGCG prevented UV-induced suppression of the contact hypersensitivity in wild-type (WT) mice but did not prevent it in IL-12 KO mice. Injection of anti-IL-12 monoclonal antibody to WT mice blocked the preventive effect of EGCG on UV-induced immunosuppression. EGCG reduced or repaired UV-induced DNA damage in skin faster in WT mice as shown by reduced number of CPDs + cells and reduced the migration of CPD + antigen-presenting cells from the skin to draining lymph nodes. In contrast, this effect of EGCG was not seen in IL-12 KO mice. Further, EGCG was able to repair UV-induced CPDs in XPA -proficient cells obtained from healthy person but did not repair in XPA -deficient cells, indicating that nucleotide excision repair mechanism is involved in DNA repair. Conclusions: These data identify a new mechanism by which EGCG prevents UV-induced immunosuppression, and this may contribute to the chemopreventive activity of EGCG in prevention of photocarcinogenesis.