Pathological role of large intestinal IL-12p40 for the induction of Th2-type allergic diarrhea
Pathological role of large intestinal IL-12p40 for the induction of Th2-type allergic diarrhea
复制标题
DOI：
10.1016/s0002-9440(10)63219-1
复制
发表时间：
2004-04-01
影响因子：
6
通讯作者：
Kiyono, H
中科院分区：
文献类型：
--
作者：
Hino, A;Kweon, MN;Kiyono, H
IL-12由两个二硫化物连接的亚基p40和P35组成，它们形成功能活跃的异源二聚体，诱导Th1细胞。与IL-12异源二聚体相比，p40单体和同源二聚体对Th1细胞具有抑制作用，导致Th2环境的产生。虽然IL-12p40在体外可作为IL-12p70的拮抗剂，但目前还没有证据表明IL-12p40在体内是否具有功能。我们现在报道IL-12p40在肠道变应性疾病中起重要的病理作用。IL-12p40蛋白在过敏性腹泻小鼠大肠（而非小肠）上皮细胞、树突状细胞和巨噬细胞中高表达。有趣的是，用抗il -12p40单抗中和可以降低发病率并延缓疾病发展的发生。抗il -12p40单抗小鼠血清中卵白蛋白（OVA）特异性IgE抗体水平低于对照单抗小鼠。抗il -12p40单抗小鼠大肠单核细胞分泌Th2细胞因子和eotaxin明显减少。最后，去除IL-12p40基因导致疾病发展完全抑制。这些结果表明，IL-12p40的过表达是过敏性腹泻小鼠大肠中th2型显性环境产生的重要促成因素。
IL-12 consists of two disulfide-linked subunits, p40 and P35, that form functionally active heterodimers for the induction of Th1 cells. In contrast to IL-12 heterodimers, p40 monomers and homodimers possess inhibitory effects on Th1 cells leading to the creation of a Th2 environment. Although it has been shown that IL-12p40 acts as antagonist of IL-12p70 in vitro, no evidence is currently available whether IL-12p40 is functional in vivo. We now report that IL-12p40 plays an important pathological role in an intestinal allergic disease. A high expression of IL-12p40 protein wits demonstrated in epithelial cells, dendritic cells, and macrophages in large but not small intestine of allergic diarrhea-induced mice. Interestingly, neutralization with anti-IL-12p40 mAbs reduced the incidence and delayed the onset of disease development. Lower levels of ovalbumin (OVA)specific IgE Abs in serum were detected in anti-IL-12p40 mAb-treated mice than in control Ab-treated mice. The secretion of Th2 cytokines and eotaxin by the mononuclear cells isolated from the large intestine of anti-IL-12p40 mAb-treated mice was significantly decreased. Finally, the removal of the IL-12p40 gene resulted in complete inhibition of disease development. These results show that over-expression of IL-12p40 is an important contributing factor for the generation of the dominant Th2-type environment in the large intestine of mice with allergic diarrhea.