IL-12 prevents the inhibitory effects of cis-urocanic acid on tumor antigen presentation by Langerhans cells: implications for photocarcinogenesis.
UV radiation induces skin cancer primarily by its DNA-damaging properties, but also by its capacity to suppress the immune system. The photoisomer of urocanic acid (UCA), cis-UCA, is an important mediator of UV-induced immunosuppression and is involved in the inhibition of tumor immunity. The immunomodulatory cytokine IL-12 is known to counteract many of the immunosuppressive effects of UV radiation, including UV-induced immune tolerance. In this study, we addressed whether IL-12 also reverts the immunosuppressive activities of cis-UCA. Cis-UCA inhibits the ability of Langerhans cells to present tumor Ags for primary and secondary tumor immune responses. IL-12 treatment completely prevented the suppression by cis-UCA. IL-12 also protected mice from cis-UCA-induced suppression of contact hypersensitivity responses. To study the effects of cis-UCA on Ag-processing and Ag-presenting function in vitro, Langerhans cells were treated with UCA isomers and incubated with OVA or OVA peptide(323-339) before exposure to OVA-specific transgenic T cells. Cis-, but not trans-UCA suppressed Ag presentation, which was completely reversed upon addition of IL-12. Since these findings suggest that cis-UCA may play an important role in photocarcinogenesis by inhibiting a tumor immune response, mice were chronically UVB irradiated to induce skin cancer. Whereas all mice in the control groups developed tumors, mice treated with a mAb with specificity for cis-UCA showed a significantly reduced tumor incidence. These data strongly indicate the importance of cis-UCA during photocarcinogenesis and support the concept of counteracting cis-UCA as an alternative strategy to prevent UV-induced skin cancer, possibly via the application of IL-12.
Beissert
S
S
Department of Dermatology, University of Münster, Münster, Germany. beisser@uni-muenster.de
Rühlemann
D
D
Mohammad
T
T
Grabbe
S
S
El-Ghorr
A
A
Norval
M
M
Morrison
H
H
Granstein
R D
RD
Schwarz
T
T
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D003877:Dermatitis, Contact / Q000276:immunology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007106:Immune Sera / Q000008:administration & dosage; D007116:Immunization, Passive; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000502:physiology*; D007801:Langerhans Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009381:Neoplasms, Radiation-Induced / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology / Q000517:prevention & control; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D014560:Urocanic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D007106:Immune Sera; D007166:Immunosuppressive Agents; D018664:Interleukin-12; D014560:Urocanic Acid