IL-23 antagonizes UVR-induced immunosuppression through two mechanisms: reduction of UVR-induced DNA damage and inhibition of UVR-induced regulatory T cells.
UVR-induced DNA damage is the major molecular trigger for photoimmunosuppression. The cytokines IL-12 and IL-18, which reduce DNA damage through induction of DNA repair, prevent UVR-induced immunosuppression. IL-12 but not IL-18 can break established UVR-induced immunotolerance through modulation of regulatory T cells (Treg). IL-23 is related to IL-12 by sharing the p40 subunit. Hence, we studied whether (i) IL-23 can reduce UVR-induced DNA damage and thereby prevent UVR-induced immunosuppression and (ii) can suppress the activity of Treg. IL-23 reduced UVR-induced apoptosis of keratinocytes. Injection of IL-23 into UVR-exposed mice diminished the number of apoptotic keratinocytes and the amounts of DNA damage. This was not observed in DNA repair-deficient xeroderma pigmentosum A knock-out mice (Xpa-KO mice), implying that IL-23 reduces DNA damage through induction of DNA repair. Similarly, UVR-mediated suppression of the induction of contact hypersensitivity was prevented on injection of IL-23 in wild-type but not in Xpa-KO mice. However, in contrast to IL-18, IL-23 inhibited the activity of UVR-induced Treg as demonstrated by adoptive transfer experiments. Our data indicate that IL-23, similar to IL-12 and IL-18, can reduce UVR-induced DNA damage and thereby prevent immunosuppression. IL-23 shares with IL-12 the still unique capacity to restore suppressed immune responses because of its effect on Treg.
Majewski
Sebastian
S
Department of Dermatology, University Kiel, Kiel, Germany.
Jantschitsch
Christian
C
Maeda
Akira
A
Schwarz
Thomas
T
Schwarz
Agatha
A
D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D005260:Female; D007166:Immunosuppressive Agents / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics
D007166:Immunosuppressive Agents; D020382:Interleukin-18; D053759:Interleukin-23; D018664:Interleukin-12