Massive but selective cytokine dysregulation in the colon of IL-10-/- mice revealed by multiplex analysis
Massive but selective cytokine dysregulation in the colon of IL-10-/- mice revealed by multiplex analysis
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DOI：
10.1093/intimm/dxm126
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发表时间：
2008-01-01
影响因子：
4.4
通讯作者：
Klein, John R.
中科院分区：
文献类型：
--
作者：
Montufar-Solis, Dina;Schaefer, Jeremy;Klein, John R.
IL-10 缺陷小鼠由于细胞因子调节失败而患上小肠结肠炎；然而，该应对措施的全部范围仍然不明确。使用多重分析来量化结肠白细胞产生的 23 种调节细胞因子和效应细胞因子的活性，我们证明了 7 至 27 周龄 IL-10-/- 小鼠中 18 种细胞因子的巨大失调过程。其中，IL-12p40、IL-6、粒细胞巨噬细胞集落刺激因子、IFN-γ、IL-13 和单核细胞趋化蛋白-1 (MCP-1) 与病理学的单一相关性最高 (r = 0.7766-0.7016)。重要的是，这些细胞因子与多达 10 种其他细胞因子之间存在很强的关联性 (r = 0.7071-0.9074)，表明随着疾病进展，细胞因子具有高度复杂性。 IL-17 值得注意的是，它是由病理从轻度到重度不等的 IL-10-/- 小鼠的结肠白细胞产生的，尽管缺乏病理的健康 IL-10-/- 小鼠不会产生 IL-17。肿瘤坏死因子 α (TNF α) 本身与病理学关系不大 (r = 0.6340)，排名倒数第六，尽管它与其他 12 种细胞因子的合成具有很强的交叉相关性，这意味着与 TNF α 相关的破坏性作用可能是由于多种细胞因子活性的相互作用造成的。 IL-23 表达与病理学无关，这可能表明 IL-23 参与炎症的引发，但与炎症的持续存在无关。四种细胞因子（IL-2、IL-3、IL-4 和 IL-5）在 IL-10-/- 小鼠中仍呈阴性，表明细胞因子失调并不普遍。这些发现强调需要更好地了解慢性炎症中的细胞因子网络，并为联合免疫疗法治疗肠道炎症提供了理论基础。
IL-10-deficient mice develop enterocolitis due to a failure of cytokine regulation; however, the full scope of that response remains poorly defined. Using multiplex analysis to quantify the activity of 23 regulatory and effector cytokines produced by colonic leukocytes, we demonstrate a vast dysregulation process of 18 cytokines in IL-10-/- mice from 7 to 27 weeks of age. Of those, IL-12p40, IL-6, granulocyte macrophage colony-stimulating factor, IFN-gamma, IL-13 and monocyte chemoattractant protein-1 (MCP-1) had the highest single correlations with pathology (r = 0.7766-0.7016). Importantly, there were strong associations (r = 0.7071-0.9074) between those cytokines and as many as 10 additional cytokines, indicating a high degree of cytokine complexity as disease progressed. IL-17 was notable in that it was produced at high levels by colonic leukocytes from IL-10-/- mice with pathology ranging from mild to severe, though it was not produced by healthy IL-10-/- mice lacking pathology. Tumor necrosis factor alpha (TNF alpha) by itself displayed only a modest association with pathology (r = 0.6340), ranking sixth lowest, though it cross-correlated strongly with the synthesis of 12 other cytokines, implying that the destructive effects associated with TNF alpha may be due to interactions of multiple cytokine activities. IL-23 expression did not correlate with pathology, possibly suggesting that IL-23 is involved in the initiation but not the perpetuation of inflammation. Four cytokines (IL-2, IL-3, IL-4 and IL-5) remained negative in IL-10-/- mice, demonstrating that cytokine dysregulation was not universal. These findings emphasize the need to better understand cytokine networks in chronic inflammation and they provide a rationale for combining immunotherapies in the treatment of intestinal inflammation.