Clarification of the mechanism of allergic diseases based on the analyses of the mechanism of signal transduction of interleukin-4 and-13

虽然白介素4和白介素13参与了变态反应性疾病的发病机制，但其确切的发病机制仍不十分清楚。为了阐明这一点，我们先前通过微阵列方法在支气管上皮细胞中鉴定了IL-4或IL-13诱导的基因。我们证明了已鉴定基因中的鳞状细胞癌抗原(SCCA)1和SCCA2在哮喘患者的支气管组织和血清中的表达增强。在本研究中，我们分析了SCCA1和SCCA2的功能，虽然SCCA1和SCCA2属于丝氨酸蛋白家族，但我们发现这些分子与其他蛇类相比，对半胱氨酸蛋白酶有抑制作用。特别值得注意的是，我们发现SCCA2抑制了Der p 1的半胱氨酸蛋白酶活性，Der p 1是一种主要的粉尘变应原。这些结果表明，IL-4和IL-13通过诱导半胱氨酸蛋白酶抑制剂在防御外源性半胱氨酸蛋白酶的机制中发挥作用。此外，我们还成功地获得了一株SCCA2突变体，其对Der p1的抑制活性强于野生型SCCA2。这些结果表明，我们有可能将SCCA2本身或其类似物应用于研制一种抗粉尘过敏反应的试剂。

Although it is well known that interleukin(IL)-4 and IL- 13 are involved in the pathogenesis of allergic diseases, the precise mechanism of these diseases is still obscure. To clarify this point, we previously identified IL-4- or IL-13-inducible genes in bronchial epithelial cells by the microarray approach. We demonstrated that expression of the squamous cell carcinoma antigen(SCCA) 1 and SCCA2 included in the identified genes was augmented in the bronchial tissues and the serum derived from asthma patients. In this study, we analyzed the functional roles of SCCA1 and SCCA2.Although SCCA1 and SCCA2 belong to the serpin family, we found that these molecules inhibited cysteine proteases, in contrast to other serpins. Particularly, it is of note that we showed that SCCA2 inhibited the cysteine proteinase activity of Der p 1,a major mite allergen. These results indicated that IL-4 and IL-13 play a role in the defense mechanism against external cysteine proteinases by inducing cysteine proteinase inhibitors. Furthermore, we succeeded in generating a SCCA2 mutant whose inhibitory activity against Der p 1 was stronger than the wild SCCA2. These results indicated the possibility that we may apply SCCA2 itself or its analogue to development of a reagent against allergic diseases induced by mites.