Overexpression of Interleukin-23, but Not Interleukin-17, as an Immunologic Signature of Subdinical Intestinal Inflammation in Ankylosing Spondylitis
Overexpression of Interleukin-23, but Not Interleukin-17, as an Immunologic Signature of Subdinical Intestinal Inflammation in Ankylosing Spondylitis
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DOI：
10.1002/art.24389
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发表时间：
2009-04-01
影响因子：
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通讯作者：
Triolo, Giovanni
中科院分区：
文献类型：
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作者：
Ciccia, Francesco;Bombardieri, Michele;Triolo, Giovanni
Objective.亚临床肠道炎症在脊柱关节炎中很常见，但这一过程的免疫异常尚不明确。白细胞介素-23（IL-23）/Th 17轴的紊乱已成为慢性炎症的基本触发因素。本研究旨在探讨IL-23/Th 17相关分子在克罗恩病（CD）和强直性脊柱炎（AS）亚临床肠道炎症中的表达和组织分布。从12例CD患者、15例AS患者和13例对照者的肠道活检样本中进行Th 1/Th 2和IL-23/Th 17应答的定量基因表达分析。采用免疫组织化学法检测IL-23在组织中的分布，并对IL-23产生细胞进行鉴定。我们证明了一个强大的和显着的上调IL-23 p19转录在回肠末端的患者与AS和CD患者。AS和CD患者炎症粘膜中浸润的单核细胞样细胞大量产生IL-23。值得注意的是，我们还确定潘氏细胞作为AS患者、CD患者和正常对照中IL-23的主要来源。与CD不同，在AS患者中，IL-23与IL-17和IL-17诱导细胞因子IL-6和IL-1 β的上调无关。最后，虽然Th 1相关细胞因子干扰素-γ、IL-12 p35和IL-27 p28仅在CD患者中过表达，但IL-4、IL-5和STAT-6在AS患者中也显著升高。我们的研究结果表明，IL-23的过度表达，而不是IL-17，是AS亚临床肠道炎症的关键特征。在生理和病理条件下，将常驻潘氏细胞鉴定为IL-23的关键来源，这强烈表明IL-23是肠道粘膜免疫的主要调节剂，为所报道的IL-23受体多态性与肠道炎症之间的关联提供了病理生理学意义。
Objective. Subclinical gut inflammation is common in spondylarthritis, but the immunologic abnormalities underlying this process are undefined. Perturbation of the interleukin-23 (IL-23)/Th17 axis has emerged as a fundamental trigger of chronic inflammation. This study was undertaken to investigate the expression and tissue distribution of IL-23/Th17-related molecules in Crohn's disease (CD) and in subclinical gut inflammation in ankylosing spondylitis (AS).Methods. Quantitative gene expression analysis of Th1/Th2 and IL-23/Th17 responses was performed in intestinal biopsy samples obtained from 12 patients with CD, 15 patients with AS, and 13 controls. IL-23 tissue distribution and identification of IL-23-producing cells were evaluated by immunohistochemistry.Results. We demonstrated a strong and significant up-regulation of IL-23p19 transcripts in the terminal ileum in patients with AS and patients with CD. IL-23 was abundantly produced by infiltrating monocyte-like cells in inflamed mucosa from AS and CD patients. Notably, we also identified Paneth cells as a major source of IL-23 in patients with AS, patients with CD, and normal controls. Unlike CD, in AS patients, IL-23 was not associated with up-regulation of IL-17 and the IL-17-inducing cytokines IL-6 and IL-1 beta. Finally, while the Th1-related cytokines interferon-gamma, IL-12p35, and IL-27p28 were overexpressed only in CD patients, IL-4, IL-5, and STAT-6 were also significantly increased in AS patients.Conclusion. Our findings indicate that overexpression of IL-23, but not IL-17, is a pivotal feature of subclinical gut inflammation in AS. Identification of resident Paneth cells as a pivotal source of IL-23 in physiologic and pathologic conditions strongly suggests that IL-23 is a master regulator of gut mucosal immunity, providing a pathophysiologic significance to the reported association between IL-23 receptor polymorphisms and intestinal inflammation.