IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions

Kojima, Hiroshi; Tsutsui, Hiroko; Murakami, Takaaki; Yumikura‐Futatsugi, Shizue; Yamanaka, Kei; Tanaka, Minoru; Iwakura, Yoichiroh; Suzuki, Noboru; Takeda, Kiyoshi; Akira, Shizuo; Nakanishi, Kenji; Mizutani, Hitoshi

doi:10.1073/pnas.152337799

Cited by 247 publications

(209 citation statements)

References 46 publications

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“…Accordingly, development of atopic like dermatitis in transgenic mice overexpressing caspase-1, the enzyme that cleaves IL-18 into its active form, is critically dependent on IL-18 (41). IL-18 is secreted by a variety of cells including macrophages, dendritic cells, and epithelial cells (23).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…3C) and the skin lesions in EP Ϫ/Ϫ mice were mostly restricted to faces and ears, suggesting that IL-1␣ release by repeated groominginduced injury may accumulate IL-18 in the skin of EP Ϫ/Ϫ mice, resulting in the initiation of development of dermatitis in EP Ϫ/Ϫ mice (22). IL-1␣ alone did not induce the active form of IL-18 by primary keratinocytes (data not shown), suggesting that some particular signals, in addition to IL-1␣, may be necessary for the production of the active form of IL-18 by keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of IL-1␣ in murine epidermis produces inflammatory skin lesions, indicating the critical role of IL-1␣ in skin inflammation (21). On the other hand, IL-18 is stored as a biologically inactive precursor form in keratinocytes, and overexpression of IL-18 in the mouse skin was reported to induce inflammatory skin lesions without inducing allergen-specific IgE production (22).…”

mentioning

confidence: 99%

Dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage

Shirasawa

Sugiyama

Baba

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Epidermal growth factor (EGF) family members, including epiregulin (EP), play a fundamental role in epithelial tissues; however, their roles in immune responses and the physiological role of EP remain to be elucidated. The skin has a versatile system of immune surveillance. Biologically active IL-1␣ is released to extracellular space upon damage from keratinocytes and is a major player in skin inflammation. Here, we show that EP is expressed not only in keratinocytes but also in tissue-resident macrophages, and that EP-deficient (EP ؊/؊ ) mice develop chronic dermatitis. Wound healing in the skin in EP ؊/؊ mice was not impaired in vivo, nor was the growth rate of keratinocytes from EP ؊/؊ mice different from that of WT mice in vitro. Of interest is that in WT keratinocytes, both IL-1␣ and the secreted form of EP induced down-regulation of IL-18 mRNA expression, which overexpression in the epidermis was reported to induce skin inflammation in mice, whereas the downregulation of IL-18 induced by IL-1␣ was impaired in EP ؊/؊ keratinocytes. Although bone marrow transfer experiments indicated that EP deficiency in non-bone-marrow-derived cells is essential for the development of dermatitis, production of proinflammatory cytokines by EP ؊/؊ macrophages in response to Toll-like receptor agonists was much lower, compared with WT macrophages, whose dysfunction in EP ؊/؊ macrophages was not compensated by the addition of the secreted form of EP. These findings, taken together, suggested that EP plays a critical role in immune͞inflammatory-related responses of keratinocytes and macrophages at the barrier from the outside milieu and that the secreted and membranebound forms of EP have distinct functions.T he system of epidermal growth factor (EGF) superfamily (1) and EGF receptor (EGFR) family, including EGFR (ErbB1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) (2), play a fundamental role in epithelial tissues. EGF family members, including EGF, transforming growth factor-␣, amphiregulin, heparinbinding EGF (HB-EGF), epiregulin (EP), and other members, regulate these receptors by inducing their homo-and͞or heterooligomerization (2, 3). EGF family members vary in their ability to activate distinct ErbB heterodimers, and this mechanism may, in part, account for the differences in their bioactivities (4-7).The membrane-anchored precursor of the EGF family is enzymatically processed externally to release a mature soluble form that acts as autocrine and͞or paracrine growth factor (8, 9), whereas some members of the EGF family act in the membrane-anchored form (8, 10). A bioactive transmembrane precursor, pro-HB-EGF, was suggested to induce growth inhibition or apoptosis rather than the proliferative response induced by soluble HB-EGF (10). EP (11-17) acts as an autocrine growth factor in normal human keratinocytes in vitro (15); however, its physiological role in vivo still remains to be elucidated.Keratinocytes in the epidermis play critical roles in the cutaneous immune-related responses (18) and contain biologically active ...

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“…C ontact hypersensitivity (CHS) 4 is a T cell-mediated inflammation of the skin. Clinically it is often manifested as allergic contact dermatitis, one of the most frequent dermatological problems.…”

Section: Il-18 Binding Protein Protects Against Contact Hypersensitivitymentioning

confidence: 99%

“…In humans, IL-18 is up-regulated in psoriatic lesions and serum levels of IL-18 are elevated in patients with atopic dermatitis (1)(2)(3). In the mouse, cutaneous overexpression of IL-18 induces the development of atopic dermatitis-like skin inflammation (4).…”

Section: Il-18 Binding Protein Protects Against Contact Hypersensitivitymentioning

confidence: 99%

IL-18 Binding Protein Protects Against Contact Hypersensitivity

Plitz¹,

Saint-Mézard

Satho

et al. 2003

The Journal of Immunology

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Allergic contact dermatitis, the clinical manifestation of contact hypersensitivity, is one of the most common disorders of the skin. It is elicited upon multiple cutaneous re-exposure of sensitized individuals to the sensitizing agent. In this study, we demonstrate that using IL-18 binding protein (IL-18BP) to neutralize IL-18 significantly reduced clinical symptoms in a murine model of contact hypersensitivity. Furthermore, IL-18BP alleviated the relapses during established disease, as indicated by significant protection during re-exposure of mice that had previously undergone a contact hypersensitivity response without treatment. Although edema was not influenced, IL-18BP reduced the number of T cells homing to sites of inflammation, resulting in diminished local production of IFN-γ. Thus, by preventing the accumulation of effector T cells to the target tissue, IL-18BP appears to be a potent protective mediator to counter skin inflammation during contact hypersensitivity. Taken together with the evidence that IL-18 is present in tissue samples of the human disease, our data reinforces IL-18BP as a candidate for this therapeutic indication.

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IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions

Cited by 247 publications

References 46 publications

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

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

Dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage

IL-18 Binding Protein Protects Against Contact Hypersensitivity

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