The C10/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-Induced inflammation and remodeling
The C10/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-Induced inflammation and remodeling
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DOI：
10.4049/jimmunol.172.3.1872
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发表时间：
2004-02-01
影响因子：
4.4
通讯作者：
Elias, JA
中科院分区：
文献类型：
--
作者：
Ma, B;Zhu, Z;Elias, JA
IL-13 是一种有效的炎症和组织重塑刺激剂，在多种人类疾病的发病机制中发挥着关键作用。为了进一步了解这些反应，我们进行了研究以确定趋化因子 C10/CCL6 在 IL-13 诱导的小鼠肺部改变的发病机制中的作用。 IL-13 是 C10/CCL6 mRNA 和蛋白质的非常有效的刺激剂，IL-13 诱导的炎症、肺泡重塑和顺应性改变在 C10/CCL6 中和后显着改善。使用抗 C10/CCL6 治疗可降低野生型小鼠肺中编码基质金属蛋白酶-2 (MMP-2)、MMP-9 和金属蛋白酶-4 组织抑制剂 (TIMP-4) 的 mRNA 水平。 C10/CCL6 中和还降低了 IL-13 刺激单核细胞趋化蛋白-1、巨噬细胞炎症蛋白-1α、MMP-2、MMP-9 和组织蛋白酶-K、-L 和 -S 产生的能力，以及 IL-13 抑制 α1-抗胰蛋白酶的能力。根据这些发现，CCR1（一种假定的 C10/CCL6 受体）的靶向无效突变也减少了 IL-13 诱导的炎症和肺泡重塑，并引起趋化因子、蛋白酶和抗蛋白酶的变化，与 C10/CCL6 中和后所见的变化相当。这些 C10/CCL6 和 CCR1 操作没有改变转基因 IL-13 的产生。这些研究表明，IL-13 是 C10/CCL6 的有效刺激剂，并强调了 C10/CCL6 和 CCR1 信号传导在 IL-13 诱导的肺部表型发病机制中的重要性。他们还描述了 C10/CCL6 靶基因级联反应，其中 C10/CCL6 诱导对于选定趋化因子（单核细胞趋化蛋白-1 和 MIP-1α）和蛋白酶（MMP-2、MMP-9 和组织蛋白酶-K、-L 和 -S）的最佳 IL-13 刺激以及 α1-抗胰蛋白酶的抑制是必需的。
IL-13 is a potent stimulator of inflammation and tissue remodeling that plays a key role in the pathogenesis of a wide variety of human disorders. To further understand these responses, studies were undertaken to define the role(s) of the chemokine C10/ CCL6 in the pathogenesis of IL-13-induced alterations in the murine lung. IL-13 was a very potent stimulator of C10/CCL6 mRNA and protein, and IL-13-induced inflammation, alveolar remodeling, and compliance alterations were markedly ameliorated after C10/CCL6 neutralization. Treatment with anti-C10/CCL6 decreased the levels of mRNA encoding matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of metalloproteinase-4 (TIMP-4) in lungs from wild-type mice. C10/CCL6 neutralization also decreased the ability of IL-13 to stimulate the production of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, MMP-2, MMP-9, and cathepsins-K, -L, and -S and the ability of IL-13 to inhibit alpha1-antitrypsin. In accord with these findings, a targeted null mutation of CCR1, a putative C10/CCL6 receptor, also decreased IL-13-induced inflammation and alveolar remodeling and caused alterations in chemokines, proteases, and antiproteases comparable to those seen after C10/CCL6 neutralization. These C10/CCL6 and CCR1 manipulations did not alter the production of transgenic IL-13. These studies demonstrate that IL-13 is a potent stimulator of C10/CCL6 and highlight the importance of C10/CCL6 and signaling via CCR1 in the pathogenesis of the IL-13-induced pulmonary phenotype. They also describe a C10/CCL6 target gene cascade in which C10/CCL6 induction is required for optimal IL-13 stimulation of selected chemokines (monocyte chemoattractant protein-1 and MIP-1alpha) and proteases (MMP-2, MMP-9, and cathepsins-K, -L, and -S) and the inhibition of alpha1-antitrypsin.