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

虽然众所周知白细胞介素（IL）-4和IL- 13参与了变态反应性疾病的发病机制，但这些疾病的确切机制仍然不清楚。为了阐明这一点，我们以前确定了IL-4或IL-13诱导基因在支气管上皮细胞的微阵列方法。我们证明，鳞状细胞癌抗原（SCCA）1和SCCA 2的表达，包括在确定的基因中的支气管组织和血清来源于哮喘患者增加。本研究对SCCA 1和SCCA 2的功能进行了分析。虽然SCCA 1和SCCA 2属于丝氨酸蛋白酶抑制剂家族，但与其他丝氨酸蛋白酶抑制剂相比，它们对半胱氨酸蛋白酶具有抑制作用。特别是，值得注意的是，我们发现SCCA 2抑制了Der p 1（一种主要的螨过敏原）的半胱氨酸蛋白酶活性。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而在对外部半胱氨酸蛋白酶的防御机制中发挥作用。此外，我们成功地产生了SCCA 2突变体，其对Der p 1的抑制活性强于野生型SCCA 2。这些结果表明，我们可能会应用SCCA 2本身或其类似物开发的试剂，对过敏性疾病的螨诱导。

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.