Mao X Q, Kawai M, Yamashita T, Enomoto T, Dake Y, Sasaki S, Kataoka Y, Fukuzumi T, Endo K, Sano H, Aoki T, Kurimoto F, Adra C N, Shirakawa T, Hopkin J M
Experimental Medicine Unit, University of Wales Swansea, Swansea, United Kingdom.
Biochem Biophys Res Commun. 2000 Sep 24;276(2):607-12. doi: 10.1006/bbrc.2000.3516.
Genes of the IL-1 family encode three different peptides, IL-1alpha, IL-1beta, and IL-1Ra, respectively. IL-1 operates through IL-1RI, and is involved in airway inflammation in asthmatic subjects, whereas IL-1Ra appears to be a specific competitive inhibitor of IL-1. All genes are on chromosome 2q12-21 where genomewide searches have identified linkage for asthma. To test whether variants of IL-1 relate to asthma, we conducted a genetic association study in a Japanese population. We show that the A2 allele of IL1RN (encoding IL-1Ra) associates with nonatopic asthma [OR = 5.71, 95% CI: 1.63-19. 8, Pc = 0.007]. Both atopic and nonatopic asthmatics with the A2 allele had significantly lower serum IL-1Ra levels in both types of asthmatics. Peripheral blood cells from asthmatics with A2 alleles, however, produced as much IL-1 as did those with A1 homozygotes. Since Th1 and Th2 cytokines differentially regulate the ratio between IL-1beta and IL-1Ra, these findings suggest that dysregulation of IL-1beta/IL-1Ra, probably due to interaction between epithelium and immuno-competent cells in the airway, is important in asthma inflammation.
白细胞介素-1（IL-1）家族的基因分别编码三种不同的肽，即IL-1α、IL-1β和IL-1受体拮抗剂（IL-1Ra）。IL-1通过IL-1受体I型（IL-1RI）发挥作用，并参与哮喘患者的气道炎症，而IL-1Ra似乎是IL-1的特异性竞争性抑制剂。所有这些基因都位于2号染色体的q12-21区域，全基因组搜索已在此处确定了与哮喘的连锁关系。为了检验IL-1的变异体是否与哮喘相关，我们在日本人群中进行了一项基因关联研究。我们发现，IL1RN（编码IL-1Ra）的A2等位基因与非特应性哮喘相关[比值比（OR）=5.71，95%置信区间（CI）：1.63 - 19.8，校正P值（Pc）=0.007]。在两种类型的哮喘患者中，携带A2等位基因的特应性和非特应性哮喘患者的血清IL-1Ra水平均显著较低。然而，携带A2等位基因的哮喘患者外周血细胞产生的IL-1与A1纯合子患者产生的一样多。由于辅助性T细胞1型（Th1）和辅助性T细胞2型（Th2）细胞因子对IL-1β和IL-1Ra之间的比例有不同的调节作用，这些发现表明，IL-1β/IL-1Ra的失调，可能是由于气道上皮细胞与免疫活性细胞之间的相互作用，在哮喘炎症中起重要作用。
