Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts
Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts
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DOI：
10.1053/j.gastro.2005.06.071
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发表时间：
2005-09-01
期刊：
影响因子：
29.4
通讯作者：
Fujiyama, Y
中科院分区：
文献类型：
--
作者：
Andoh, A;Zhang, ZB;Fujiyama, Y
背景与目的：白细胞介素 (IL)-22 是 IL-10 亚家族的成员，是最近发现的一种 T 细胞衍生的细胞因子。我们研究了炎症性肠病 (IBD) 患者发炎粘膜中 IL-22 的表达，并分析了其在人结肠上皮下肌成纤维细胞 (SEMF) 中的生物学活性。方法：通过免疫组织化学方法评估粘膜 IL-22 表达。通过 cDNA 微阵列、Northern 印迹、酶联免疫吸附测定和电泳凝胶迁移率变动测定 (EMSA) 研究 IL-22 对结肠 SEMF 的影响。结果：在正常结肠粘膜中未检测到IL-22。在 IBD 粘膜中，CD4 阳性 T 细胞中可检测到 IL-22 表达。 IL-22 阳性细胞在溃疡性结肠炎中增加，在克罗恩病中更是如此。 IL-22 受体表达与 SEMF 标记共定位。 IL-22 不调节 SEMF 增殖和胶原蛋白合成。 cDNA 微阵列分析表明，在结肠 SEMF 中，IL-22 增加了炎症细胞因子（IL-6、IL-8、IL-11 和白血病抑制因子 [LIF]）、趋化因子和基质金属蛋白酶的信使 RNA (mRNA) 表达。 IL-22在1小时内诱导核因子(NF)-κB和激活蛋白(AP)-1的激活，并且阻断NF-κB和AP-1激活显着降低IL-22对IL-6、IL-8、IL-11和LIF mRNA的诱导。 MAP 激酶抑制剂（PD98059、U0216 和 SB202190）显着降低 IL-22 诱导的细胞因子分泌。 IL-17 加 IL-22 或 IL-19 加 IL-22 的组合可加性上调细胞因子的分泌。结论：源自活化 T 细胞的 IL-22 作用于 SEMF，引发促炎细胞因子和基质降解分子的表达，表明 IBD 中的促炎/重塑作用。
Background & Aims: Interleukin (IL)-22, a member of the IL-10 subfamily, is a recently identified T-cell-derived cytokine. We investigated IL-22 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and analyzed its biologic activities in human colonic subepithelial myofibroblasts (SEMFs). Methods: Mucosal IL-22 expression was evaluated by immunohistochemical procedures. The effects of IL-22 on colonic SEMFs were investigated by cDNA microarrays, Northern blots, enzyme-linked immunosorbent assay, and electrophoretic gel mobility shift assays (EMSAs). Results : IL-22 was not detectable in normal colonic mucosa. In IBD mucosa, IL-22 expression was detectable in CD4-positive T cells. IL-22-positive cells were increased in ulcerative colitis and even more so in Crohn's disease. IL-22 receptor expression colocalized with a marker of SEMFs. IL-22 did not modulate SEMF proliferation and collagen synthesis. cDNA microarray analyses demonstrated that, in colonic SEMFs, IL-22 increased the messenger RNA (mRNA) expression of inflammatory cytokines (IL-6, IL-8, IL-11, and leukemia inhibitory factor [LIF]), chemokines, and matrix metalloproteinases. IL-22 induced an activation of nuclear factor (NF)-kappa B and activating protein (AP)-1 within I hour, and a blockade of NF-kappa B and AP-1 activation markedly reduced IL-22 induction of IL-6, IL-8, IL-11, and LIF mRNA. MAP-kinase inhibitors (PD98059, U0216, and SB202190) significantly reduced IL-22 induction of cytokine secretion. The combination of either IL-17 plus IL-22 or IL-19 plus IL-22 additively upregulated cytokine secretion. Conclusions: IL-22 derived from activated T cells acts on SEMFs to elicit expression of proinflammatory cytokines and matrix-degrading molecules indicating proinflammatory/remodeling roles in IBD.