Marafini Irene, Angelucci Erika, Pallone Francesco, Monteleone Giovanni
Dig Dis. 2015;33 Suppl 1:113-119. doi: 10.1159/000437106. Epub 2015 Sep 14.
In inflamed tissues of patients with inflammatory bowel disease (IBD), many immune and non-immune cells produce a vast array of cytokines, which contribute to expand and maintain the pathologic process. Key Message: Interleukin (IL)-12 and IL-23, 2 heterodimeric cytokines sharing the common p40 subunit, are over-produced in IBD and supposed to play a major role in promoting and/or sustaining the pro-inflammatory cytokine response in these disorders. IL-12 targets mostly T cells and innate lymphoid cells and through activation of Stat4 promotes T helper (Th)1 cell polarization, interferon-x03B3; and IL-21 production, while IL-23 activates Stat3 thus amplifying Th17 cell programs. These observations together with the demonstration that IL-12 and IL-23 drive pathogenic responses in animal models of colitis have paved the way for the development of IL-12p40 blockers. Two monoclonal antibodies (ustekinumab and briakinumab) targeting p40 have been tested in Crohn's disease (CD) patients. Blockade of IL-12p40 is beneficial in CD patients resistant to tumor necrosis factor (TNF) antagonists and promotes resolution of psoriatic lesions that develop in IBD patients following anti-TNF therapy.
The available human data support the pathogenic role of IL-12/IL-23 in IBD and suggest that IL-12p40 blockers could help manage some subsets of IBD patients.
在炎症性肠病（IBD）患者的炎症组织中，许多免疫细胞和非免疫细胞会产生大量细胞因子，这些细胞因子有助于扩大和维持病理过程。关键信息：白细胞介素（IL）-12和IL-23是两种共享共同p40亚基的异二聚体细胞因子，在IBD中过度产生，并被认为在促进和/或维持这些疾病中的促炎细胞因子反应中起主要作用。IL-12主要作用于T细胞和固有淋巴细胞，并通过激活Stat4促进辅助性T（Th）1细胞极化、干扰素-γ和IL-21的产生，而IL-23激活Stat3从而放大Th17细胞程序。这些观察结果以及IL-12和IL-23在结肠炎动物模型中驱动致病反应的证明，为IL-12p40阻滞剂的开发铺平了道路。两种靶向p40的单克隆抗体（优特克单抗和布罗达单抗）已在克罗恩病（CD）患者中进行了测试。阻断IL-12p40对抵抗肿瘤坏死因子（TNF）拮抗剂的CD患者有益，并可促进IBD患者在抗TNF治疗后出现的银屑病病变消退。
现有的人体数据支持IL-12/IL-23在IBD中的致病作用，并表明IL-12p40阻滞剂可能有助于治疗某些IBD患者亚群。
