Kawase Yusuke, Hoshino Tomoaki, Yokota Koichi, Kuzuhara Akemi, Kirii Yasuyuki, Nishiwaki Eiji, Maeda Yu, Takeda Junji, Okamoto Masaki, Kato Seiya, Imaizumi Toshihiro, Aizawa Hisamichi, Yoshino Kohichiro
R&D Laboratories, Nippon Organon K.K., Osaka, Japan.
J Invest Dermatol. 2003 Sep;121(3):502-9. doi: 10.1046/j.1523-1747.2003.12407.x.
Interleukin 18 induces both T helper 1 and T helper 2 cytokines, proinflammatory cytokines, chemokines, and IgE and IgG1 production. A role of interleukin 18 in inflammatory cutaneous reactions is still unclear, however. Here we generated keratin 5/interleukin 18 transgenic mice overexpressing mature murine interleukin 18 in the skin using a human keratin 5 promoter. In the contact hypersensitivity model, trinitrochlorobenzene elicited a stronger ear swelling in keratin 5/interleukin 18 transgenic mice compared with control littermate wild-type or immunoglobulin/interleukin 18 transgenic mice in which mature interleukin 18 was expressed by B and T cells under the control of the immunoglobulin promoter. Application of an irritant, croton oil, induced stronger and more sustained ear swelling in keratin 5/interleukin 18 transgenic mice than in immunoglobulin/interleukin 18 transgenic or wild-type mice. Repetitive topical application (weekly for six consecutive weeks) of trinitrochlorobenzene to their ears also elicited a stronger cutaneous inflammation in keratin 5/interleukin 18 transgenic mice than seen in immunoglobulin/interleukin 18 transgenic or wild-type mice. After these six trinitrochlorobenzene applications, the expression of interferon-gamma, interleukin-4, and CCL20 mRNA in the ear tissue was increased and dermal changes, such as acanthosis and eosinophilic, neutrophilic, and mast cell infiltration, were greater in keratin 5/interleukin 18 transgenic mice than in wild-type mice. Furthermore, the repetitive application elicited a significant increase in serum IgE levels and the number of B cells in the draining lymph node in keratin 5/interleukin 18 transgenic mice. These results suggest that overexpression of interleukin 18 in the skin aggravates allergic and nonallergic cutaneous inflammation, which is accompanied by high expression of T helper 1 and T helper 2 cytokines and chemokines in the skin.
白细胞介素18可诱导辅助性T细胞1和辅助性T细胞2细胞因子、促炎细胞因子、趋化因子以及IgE和IgG1的产生。然而，白细胞介素18在炎性皮肤反应中的作用仍不清楚。在此，我们利用人角蛋白5启动子，构建了在皮肤中过表达成熟小鼠白细胞介素18的角蛋白5/白细胞介素18转基因小鼠。在接触性超敏反应模型中，与对照同窝野生型小鼠或免疫球蛋白/白细胞介素18转基因小鼠相比，三硝基氯苯在角蛋白5/白细胞介素18转基因小鼠中引起更强的耳部肿胀，在免疫球蛋白/白细胞介素18转基因小鼠中，成熟白细胞介素18由B细胞和T细胞在免疫球蛋白启动子控制下表达。涂抹刺激性物质巴豆油后，角蛋白5/白细胞介素18转基因小鼠耳部肿胀比免疫球蛋白/白细胞介素18转基因或野生型小鼠更强且更持久。连续六周每周重复局部涂抹三硝基氯苯于其耳部，角蛋白5/白细胞介素18转基因小鼠也比免疫球蛋白/白细胞介素18转基因或野生型小鼠引发更强的皮肤炎症。在这六次三硝基氯苯涂抹后，耳部组织中γ干扰素、白细胞介素-4和CCL20 mRNA的表达增加，角蛋白5/白细胞介素18转基因小鼠的皮肤变化如棘层肥厚以及嗜酸性粒细胞、中性粒细胞和肥大细胞浸润比野生型小鼠更明显。此外，重复涂抹导致角蛋白5/白细胞介素18转基因小鼠血清IgE水平显著升高以及引流淋巴结中B细胞数量增加。这些结果表明，皮肤中白细胞介素18的过表达会加重过敏性和非过敏性皮肤炎症，同时伴有皮肤中辅助性T细胞1和辅助性T细胞2细胞因子以及趋化因子的高表达。
