Pathological Analysis of IL-18-dependently induced Atopic dermatitis mediated by Pattern Recognition Receptor Activation.

模式识别受体激活介导的 IL-18 依赖性诱导特应性皮炎的病理分析。

• 批准号: 14021126
• 负责人: NAKANISHI Kenji
• 金额: $ 39.04万
• 依托单位: Hyogo College of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14021126/
• 关键词: Allergy; Atooic Dermatitis; Innate Atonv; Th1; IL-18; IL-4; IgE; IL-13; IFN-γ; アトピー皮膚炎; NKT細胞

We previously showed that transgenic mice that over-secrete IL-18 from their epidermal cells spontaneously develop AD-like dermatitis independently of Th2 or IgE response. Furthermore, recent clinical studies revealed that serum levels of IL-18 well parallel with the disease severity of AD. Therefore, we assumed that endogenous IL-18 contributes to the development of AD, particularly intrinsic AD. It is well documented that cutaneous infection with Staphylococcus aureus exacerbates clinical AD. Recently, we demonstrated that S. aureus -derived proteinA (SpA) induces IL-18 release from skin. Here, we generated a novel intrinsic AD mouse model by daily topical application of SpA following destroying skin barrier by detergent (SDS). AD-prone NC/Nga mice showed 100% development of AD and manifested skin phenotypes with dense accumulation of leukocytes including mast cells. They exhibited elevated serum levels of IL-18 but not IgE. After application of NC/Nga mice with SpA/SDS, CD4^+ T cells prepared from their regional lymph nodes produced IFN-γ, IL-3, IL-9 and IL-13. As they produce both Th1- and Th2-cytokines, we proposed to designate them super Th1 cell. Importantly, we found that IL-18 or IL-3 blockade, completely and partly, prevented the AD development by inhibiting this T cell differentiation or the mast cell accumulation, respectively. Thus, IL-18 might be a novel target for the treatment of infection-associated AD.

我们之前表明，从表皮细胞过度分泌 IL-18 的转基因小鼠会自发地发生 AD 样皮炎，与 Th2 或 IgE 反应无关。此外，最近的临床研究表明，IL-18 的血清水平与 AD 疾病的严重程度密切相关。因此，我们假设内源性 IL-18 有助于 AD，特别是内源性 AD 的发展。有充分证据表明，金黄色葡萄球菌的皮肤感染会加剧临床 AD。最近，我们证明金黄色葡萄球菌衍生蛋白 A (SpA) 诱导皮肤释放 IL-18。在这里，我们通过清洁剂 (SDS) 破坏皮肤屏障后每天局部应用 SpA，生成了一种新型的内在 AD 小鼠模型。易患 AD 的 NC/Nga 小鼠显示 100% 发生 AD，并表现出白细胞（包括肥大细胞）密集积累的皮肤表型。他们的血清 IL-18 水平升高，但 IgE 水平没有升高。对 NC/Nga 小鼠应用 SpA/SDS 后，从其区域淋巴结制备的 CD4^+ T 细胞产生 IFN-γ、IL-3、IL-9 和 IL-13。由于它们同时产生 Th1 和 Th2 细胞因子，我们建议将它们指定为超级 Th1 细胞。重要的是，我们发现 IL-18 或 IL-3 阻断分别通过抑制 T 细胞分化或肥大细胞积累来完全和部分阻止 AD 的发展。因此，IL-18可能是治疗感染相关AD的新靶点。

项目成果

Involvement of Interleukin-18 in Acute Graft-Versus-Host Disease in Mice

• DOI: 10.1097/01.tp.0000137934.25190.b9
• 发表时间: 2004-11
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: H. Itoi;Y. Fujimori;H. Tsutsui;K. Matsui;A. Sugihara;N. Terada;T. Hada;E. Kakishita;H. Okamura;H. Hara;K. Nakanishi

Kaizu, M, et al.: "Higher levels of IL-18 circulate during primary infection of monkeys with a pathogenic SHIV than with a nonpahogenic SHIV."Virology. 313. 8-12 (2003)

Kaizu, M 等人：“与非致病性 SHIV 相比，猴子初次感染致病性 SHIV 时循环的 IL-18 水平更高。”病毒学。

Endogenous IL-6 but not TNF-a contributes to the development of TLR4/MyD88-mediated acute arthritis in mice.

内源性 IL-6 而不是 TNF-a 有助于小鼠 TLR4/MyD88 介导的急性关节炎的发生。

• 发表时间: 2005
• 期刊: Arthritis ＆ Rheum. 52
• 作者: Kyo;F.;Futani;H.;Matsui;K.;Terada;M.;Adachi;K.;Nagata;K.;Sano;H.;Tateishi;H.;Tsutsui;H.;Nakanishi;K.
• 通讯作者: K.

Ogushi, I., et al.: "Nuclear factor κ B decoy oligodeoxynucleotides prevent endotoxin-induced fatal liver failure in a murine model."Hepatology. 38. 335-344 (2003)

Ogushi, I. 等人：“核因子 κ B 诱饵寡脱氧核苷酸可预防小鼠模型中内毒素诱导的致命性肝衰竭。”《肝病学》38. 335-344 (2003)

Konishi, H.: "IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions"Proc.Natl.Acad.Sci.USA. 99. 11340-11345 (2002)

Konishi, H.：“在特定的无病原体条件下，IL-18 独立于 IgE/stat6 促进特应性皮炎样炎症性皮肤病变的自发发展”Proc.Natl.Acad.Sci.USA。