Kawaguchi Mio, Takahashi Daisuke, Hizawa Nobuyuki, Suzuki Shintaro, Matsukura Satoshi, Kokubu Fumio, Maeda Yukiko, Fukui Yoshinobu, Konno Satoshi, Huang Shau-Ku, Nishimura Masaharu, Adachi Mitsuru
First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
J Allergy Clin Immunol. 2006 Apr;117(4):795-801. doi: 10.1016/j.jaci.2005.12.1346. Epub 2006 Feb 14.
IL-17F is a recently discovered cytokine that plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. Upregulated IL17F gene expression has been observed at sites of allergen challenge in the airways of patients with asthma, suggesting that IL-17F is involved in the pathophysiology of asthma.
To investigate the role of IL-17F in asthma pathogenesis, we conducted genetic analyses of association of asthma with the common variants of IL17F, using 867 unrelated Japanese subjects.
Five polymorphisms were studied, including the coding-region sequence variant single nucleotide polymorphism rs763780 (7488T/C), which causes a His-to-Arg substitution at amino acid 161 (H161R). Functional consequences of the H161R substitution were examined by using recombinant wild-type and mutant IL-17F proteins.
Homozygosity of the H161R variant was inversely associated with asthma; the odds ratio (95% CI) for asthma was 0.06 (0.01-0.43) for the H161R homozygote compared with the wild-type homozygote (P = .0039). This result remains significant (P = .0079) after adjustment for the presence of atopy using the Mantel-Haenszel chi2 test. In addition, in vitro functional experiments demonstrated that the H161R variant of IL-17F lacks the ability to activate the mitogen-activated protein kinase pathway, cytokine production, and chemokine production in bronchial epithelial cells, unlike wild-type IL-17F. Furthermore, the H161R variant blocked induction of IL-8 expression by wild-type IL-17F.
The current findings indicate that the IL-17F H161R variant influences the risk of asthma and is a natural IL-17F antagonist, suggesting a potential role for IL-17F in the etiology of asthma.
白细胞介素-17F（IL-17F）是一种最近发现的细胞因子，它通过诱导促炎细胞因子和中性粒细胞动员细胞因子的释放而在组织炎症中发挥作用。在哮喘患者气道的变应原激发部位观察到IL-17F基因表达上调，提示IL-17F参与哮喘的病理生理过程。
为了研究IL-17F在哮喘发病机制中的作用，我们对867名无亲缘关系的日本受试者进行了哮喘与IL-17F常见变异体关联的基因分析。
研究了5个多态性，包括编码区序列变异单核苷酸多态性rs763780（7488T/C），该变异导致第161位氨基酸（H161R）由组氨酸替换为精氨酸。通过使用重组野生型和突变型IL-17F蛋白研究H161R替换的功能后果。
H161R变异体的纯合性与哮喘呈负相关；与野生型纯合子相比，H161R纯合子患哮喘的比值比（95%可信区间）为0.06（0.01 - 0.43）（P = 0.0039）。使用Mantel-Haenszel卡方检验对特应性的存在进行校正后，该结果仍然显著（P = 0.0079）。此外，体外功能实验表明，与野生型IL-17F不同，IL-17F的H161R变异体缺乏激活支气管上皮细胞中丝裂原活化蛋白激酶途径、细胞因子产生和趋化因子产生的能力。此外，H161R变异体阻断了野生型IL-17F诱导IL-8表达。
目前的研究结果表明，IL-17F H161R变异体影响哮喘风险，是一种天然的IL-17F拮抗剂，提示IL-17F在哮喘病因学中具有潜在作用。
