Prevention of UV radiation–induced immunosuppression by IL-12 is dependent on DNA repair

Schwarz, Agatha; Maeda, Akira; Kernebeck, Kerstin; Steeg, Harry van; Beissert, Stefan; Schwarz, Thomas

doi:10.1084/jem.20041212

Cited by 180 publications

(180 citation statements)

References 27 publications

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“…26 Ghoreishi et al 27 observed that regulatory T cells expanded by vitamin D 3 can only inhibit ova-specific CD8 T cells in a local, not a systemic, model. In addition, regulatory T cells may require stimulation by CPD DNA-damaged Langerhans cells migrating into sDLNs, 28 whereas this study found no requirement of CPD formation as a trigger for UVB-induced immunosuppression. Instead, it is possible that other suppressor cell types, such as UVB-induced suppressor B cells, could be indirectly inhibiting the responses of ova-specific CD8 T cells by interfering with Ag presentation in secondary lymphoid organs.…”

Section: Discussioncontrasting

confidence: 74%

“…27 Modulation of skin dendritic cells by vitamin D 3 is proposed to be important in this process; however, these cells are also prone to UVBinduced CPD. 28 Skin dendritic cells take up exogenous Ag, which they then process and present to CD4 T cells in sDLNs. To an extent, they can also cross present to CD8 T cells; however, stimulation of CD8 T cells mostly occurs after Ag transfer to CD8␣ ϩ dendritic cells in secondary lymphoid organs, which then cross present to CD8 T cells.…”

Section: Discussionmentioning

confidence: 99%

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Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

Rana

Rogers

Halliday

2011

The American Journal of Pathology

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Exposure to UVB radiation before antigen delivery at an unirradiated site inhibits functional immunological responses. Mice treated dorsally with suberythemal lowdose UVB and immunized with ova in abdominal skin generated ova-specific CD8 T cells with a significantly decreased activation, expansion, and cytotoxic activity compared with unirradiated mice. UVB also impaired the delayed-type hypersensitivity (DTH) reaction to ova. Transfer of CD4 ؉ CD25 ؉ cells from UVB-exposed mice did not suppress the ova-specific CD8 T-cell response or DTH reaction in unexposed mice, confirming that systemic low-dose UVB does not induce long-lived functional regulatory CD4 ؉ CD25 ؉ T cells. Repairing cyclobutane pyrimidine dimer-type DNA damage and blocking aryl hydrocarbon receptor signaling also did not reverse the immunosuppressive effect of UVB on ova-specific CD8 T cells and DTH, suggesting that cyclobutane pyrimidine dimers and the aryl hydrocarbon receptor are not required in systemic low-dose UVBinduced immunosuppression. The known UVB chromophore, cis-urocanic acid, and reactive oxygen species triggered the inhibition of DTH caused by UVB, but they were not involved in the modulation of CD8 T cells. These findings indicate that systemic low-dose UVB impedes the primary response of antigen-specific CD8 T cells by a novel mechanism that is independent of pathways known to be involved in systemic suppression of DTH. UVB radiation (290 to 320 nm) in natural sunlight is a potent immunosuppressant. UVB can inhibit the immune system from generating optimal responses to tumors, contact haptens, and various microbial antigens (Ags; viral, fungal, and parasitic) that can lead to exacerbated disease. Alternatively, immunosuppressive UVB can also be beneficial to control autoimmune diseases, such as psoriasis 1 and experimental autoimmune encephalomyelitis. 2 The epidermis of skin absorbs UVB through chromophores, including nuclear DNA, cytoplasmic tryptophan, and extracellular trans-urocanic acid (UCA). The molecular processes that follow trigger a cascade of events that cumulates in the phenomenon of UVB-induced immunosuppression. Some of the hallmarks of this immunosuppression include UVB-induced genetic mutations in skin cells, circulation of cis-UCA from the isomerization of trans-UCA, production of reactive oxygen species (ROS), and generation of regulatory T and B cells that can transfer suppression into UVB-naïve mice. 3 Because UVB has both detrimental and beneficial effects on the immune system, it is critical to understand the mechanisms regulated by UVB so that effective prophylactic and palliative therapies can be designed for skin diseases, such as skin cancer, and immune-mediated diseases in internal organs, such as multiple sclerosis.A previous study 4 showed that UVB can inhibit CD8 and CD4 T-cell responses to haptens. In a model of contact hypersensitivity (CHS), we demonstrated that a low dose of UVB (approximately 5 minutes of summer sunlight in Sydney, Australia, at midday) is sufficient to inhibit the activati...

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Section: Discussioncontrasting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

Rana

Rogers

Halliday

2011

The American Journal of Pathology

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“…IL-12 is also able to antagonize UV-induced immunosuppression (18 -20). This activity also appears to be related to the effect of IL-12 on DNA repair because IL-12 prevented both UV-induced suppression of the induction of contact hypersensitivity (CHS) and the depletion of Langerhans cells, the primary APC of the skin, in WT mice but not in DNA repair-deficient mice (21). Thus, these findings identified a new mechanism by which IL-12 can restore immune responses and also demonstrated a link between DNA repair and the prevention of UV-induced immunosuppression by IL-12.…”

Section: Il-18mentioning

confidence: 99%

IL-18 Reduces Ultraviolet Radiation-Induced DNA Damage and Thereby Affects Photoimmunosuppression

Schwarz

Maeda

Ständer

et al. 2006

The Journal of Immunology

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UV-induced DNA damage has been recognized as the major molecular trigger for photoimmunosuppression. IL-12 prevents UV-induced immunosuppression via its recently discovered capacity to reduce DNA damage presumably via induction of DNA repair. Because IL-18 shares some biological activities with IL-12 we studied the effect of IL-18 on UV-induced DNA damage and immunosuppression. IL-18 reduced UV-induced apoptosis of keratinocytes and supported long-term cell survival on UV exposure. Injection of IL-18 into mice that were exposed to UV radiation significantly lowered the number of apoptotic keratinocytes. Accordingly, radiation immunohistochemistry revealed reduced amounts of DNA damage in epidermal cells upon injection of IL-18. These effects were not observed in DNA repair-deficient (XpaKO) mice, indicating that IL-18 like IL-12 reduces DNA damage via DNA repair. UV-mediated suppression of the induction of contact hypersensitivity, which is known to be primarily triggered by DNA damage, was prevented upon injection of IL-18 before UV exposure in wild-type but not in XpaKO mice. In contrast to IL-12, IL-18 was not able either in wild-type or in XpaKO mice to break UV-induced immunotolerance that is mediated via regulatory T cells rather than in a DNA damage-dependent fashion. This result indicates that IL-12 is still unique in its capacity to restore immune responses because of its effect on regulatory T cells. Together, these data identify IL-18 as a further cytokine that exhibits the capacity to affect DNA repair. Though being primarily a proinflammatory cytokine through this capacity, IL-18 can also foster an immune response that is suppressed by UV radiation.

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“…8 Unfortunately, the exact mechanism by which UV modulates inflammation and immunity is not completely understood, even though understanding these events could lead to the design of novel immune-modulating treatment regimes. UV-induced DNA damage, 9 together with the production of oxidized lipids 10 and the release of immune-modulating cytokines (particularly prostaglandin E 2 , IL-4, and IL-10 11,12 ) play important roles. The downstream cellular targets of these UV-induced inflammatory mediators include dendritic cells, 13 dermal mast cells, 12 as well as regulatory T 14 and B cells.…”

mentioning

confidence: 99%

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

Byrne

Beaugie

O’Sullivan

et al. 2011

The American Journal of Pathology

105

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The cellular and molecular mechanisms by which UV radiation modulates inflammation and immunity while simultaneously maintaining skin homeostasis is complex and not completely understood. Similar to the effects of UV, IL-33 has potent immune-modulating properties that are mediated by the downstream induction of cytokines and chemokines. We have discovered that exposure of mice in vivo or human skin samples ex vivo to inflammatory doses of UVB induced IL-33 expression within the epidermal and dermal skin layers. Using a combination of murine cell lines and primary human cells, we demonstrate that both UV and the oxidized lipid platelet activating factor induce IL-33 expression in keratinocytes and dermal fibroblasts. Highlighting the significance of these results, we found that administering IL-33 to mice in vivo suppressed the induction of Th1-mediated contact hypersensitivity responses. This may have consequences for skin cancer growth because UV-induced squamous cell carcinomas that evade immunological destruction were found to express significantly higher levels of IL-33. Finally, we demonstrate that dermal mast cells and skininfiltrating neutrophils closely associate with UV-induced IL-33-expressing fibroblasts. Our results therefore identify and support a role for IL-33 as an important early danger signal produced in response to inflammation-inducing UV radiation.

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Prevention of UV radiation–induced immunosuppression by IL-12 is dependent on DNA repair

Cited by 180 publications

References 27 publications

Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

IL-18 Reduces Ultraviolet Radiation-Induced DNA Damage and Thereby Affects Photoimmunosuppression

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

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