Fuss Ivan J, Becker Christoph, Yang Zhiqiong, Groden Catherine, Hornung Ronald L, Heller Frank, Neurath Markus F, Strober Warren, Mannon Peter J
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 , USA.
Inflamm Bowel Dis. 2006 Jan;12(1):9-15. doi: 10.1097/01.mib.0000194183.92671.b6.
Interleukin (IL)-12p70 and IL-23 are key T helper-1 (TH1) cytokines that drive the inflammation seen in numerous models of intestinal inflammation. These molecules contain an identical p40 chain that is bound to a p35 chain in IL-12 and a p19 chain in IL-23, making both potentially susceptible to modulation by an anti-IL-12p40 monoclonal antibody (mAb).
In the present study, we sought to determine whether active inflammation in Crohn's disease (CD) is associated with the increased synthesis of both of these cytokines and whether patients treated with an anti-IL-12p40 mAb down-regulate IL-23 as well as IL-12p70 as previous reported.
To this end we initially determined that IL-12p70 secretion by control and CD antigen-presenting cells (macrophages) in lamina propria mononuclear populations is optimized by stimulation with CD40L and interferon-gamma. In subsequent studies using these stimulation conditions we found that patients with CD manifested both increased IL-12p70 and IL-23 secretion before anti-IL-12p40 mAb treatment and normal levels of secretion of these cytokines following cessation of treatment. Antigen-presenting cells in lamina propria mononuclear cells from ulcerative colitis patients, in contrast, produced only baseline levels of IL-23. Finally, we found that IL-23-induced T cell production of IL-17 and IL-6 are also greatly reduced after antibody treatment. The latter data are parallel to those from previous studies showing that anti-IL-12p40 down-regulates IFN-gamma and tumor necrosis factor-alpha secretion.
We conclude that CD but not ulcerative colitis is associated with high levels of both IL-12p70 and IL-23 secretion as well as the secretion of downstream effector cytokines, and that this cytokine production is down-regulated following administration of IL-12p40 mAb.
白细胞介素（IL）-12p70和IL-23是关键的辅助性T细胞1（TH1）细胞因子，在多种肠道炎症模型中驱动炎症反应。这些分子包含一条相同的p40链，该链在IL-12中与p35链结合，在IL-23中与p19链结合，这使得两者都可能易受抗IL-12p40单克隆抗体（mAb）的调节。
在本研究中，我们试图确定克罗恩病（CD）中的活动性炎症是否与这两种细胞因子合成增加相关，以及用抗IL-12p40 mAb治疗的患者是否如先前报道的那样下调IL-23以及IL-12p70。
为此，我们首先确定，通过用CD40L和干扰素-γ刺激，固有层单核细胞群体中对照和CD抗原呈递细胞（巨噬细胞）的IL-12p70分泌得到优化。在随后使用这些刺激条件的研究中，我们发现CD患者在抗IL-12p40 mAb治疗前IL-12p70和IL-23分泌均增加，治疗停止后这些细胞因子的分泌水平正常。相比之下，溃疡性结肠炎患者固有层单核细胞中的抗原呈递细胞仅产生基线水平的IL-23。最后，我们发现抗体治疗后IL-23诱导的T细胞产生的IL-17和IL-6也大大减少。后一数据与先前研究的数据平行，先前研究表明抗IL-12p40下调干扰素-γ和肿瘤坏死因子-α分泌。
我们得出结论，CD而非溃疡性结肠炎与高水平的IL-12p70和IL-23分泌以及下游效应细胞因子的分泌相关，并且在给予IL-12p40 mAb后这种细胞因子产生被下调。
