Effects of interleukin-33 on cardiac fibroblast gene expression and activity.
Effects of interleukin-33 on cardiac fibroblast gene expression and activity.
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DOI：
10.1016/j.cyto.2012.02.008
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发表时间：
2012-06
期刊：
影响因子：
3.8
通讯作者：
Carver, Wayne
中科院分区：
文献类型：
--
作者：
Zhu, Jinyu;Carver, Wayne
白细胞介素-33（IL-33）是最近描述的白细胞介素-1（IL-1）家族的成员。它是由不同类型的细胞产生的，以响应各种应激，包括出血和机械负荷增加。虽然只是最近才发现，IL-33已被证明参与几种病理过程，包括促进2型T辅助细胞相关的自身免疫性疾病。相比之下，IL-33也被发现在心血管疾病中具有保护作用。最近的研究已经表明，IL-33减弱小鼠中由增加的心血管负荷（经主动脉收缩）诱导的心脏纤维化。由于心脏纤维化在很大程度上依赖于心脏成纤维细胞产生细胞外基质的增加，我们假设IL-33直接抑制这些细胞的促纤维化活性。已经用分离的大鼠心脏成纤维细胞进行了实验，以评估IL-33对心脏成纤维细胞基因表达和功能的调节的作用，以验证这一假设。IL-33受体，白细胞介素-1受体样1（ST 2）的表达，检测在mRNA和蛋白水平在分离的成年大鼠心脏成纤维细胞。随后，检查IL-33处理（0-100 ng/ml）对细胞外基质蛋白和促炎细胞因子/趋化因子表达的影响以及对大鼠心脏成纤维细胞活性（包括增殖、胶原凝胶收缩和迁移）的影响。虽然IL-33没有直接抑制胶原蛋白I和胶原蛋白III的生产，它产生了剂量依赖性的白细胞介素-6和单核细胞趋化蛋白-1的表达增加。用IL-33处理大鼠心脏成纤维细胞也损害了这些细胞的迁移活性。进一步的实验表明，IL-33以剂量依赖的方式快速激活多种信号通路，包括细胞外信号调节激酶、p38丝裂原活化蛋白激酶、c-Jun N末端激酶和活化的B细胞（NF-k B）的核因子κ轻链增强子。用药理学抑制剂进行实验以确定特定信号传导途径在成纤维细胞对IL-33的响应中的作用。这些实验表明，p38丝裂原活化蛋白激酶和细胞外信号调节激酶的激活是至关重要的白细胞介素-6和单核细胞趋化蛋白-1响应IL-33的生产增加。这些研究表明，IL-33在成纤维细胞功能和基因表达的调节中具有重要作用。令人惊讶的是，IL-33对编码细胞外基质成分的基因的表达或对增殖（纤维化的典型标志物）没有影响。在这些研究中检测到的IL-33的主要作用包括抑制细胞迁移和激活细胞因子/趋化因子表达。先前报道的心脏纤维化的抑制可能包括涉及其他心脏细胞类型的更复杂的机制。未来的研究旨在确定IL-33对其他心脏细胞类型的影响是必要的。
Interleukin-33 (IL-33) is a recently described member of the interleukin-1 (IL-1) family. It is produced by diverse cell types in response to a variety of stresses including hemorrhage and increased mechanical load. Though only relatively recently discovered, IL-33 has been shown to participate in several pathological processes including promoting type 2 T helper cell-associated autoimmune diseases. In contrast, IL-33 has been also found to have protective effects in cardiovascular diseases. Recent studies have illustrated that IL-33 attenuates cardiac fibrosis induced by increased cardiovascular load in mice (transaortic constriction). Since cardiac fibrosis is largely dependent on increased production of extracellular matrix by cardiac fibroblasts, we hypothesized that IL-33 directly inhibits pro-fibrotic activities of these cells. Experiments have been carried out with isolated rat cardiac fibroblasts to evaluate the effects of IL-33 on the modulation of cardiac fibroblast gene expression and function to test this hypothesis. The expression of the IL-33 receptor, interleukin-1 receptor-like 1 (ST2), was detected at the mRNA and protein levels in isolated adult rat cardiac fibroblasts. Subsequently, the effects of IL-33 treatment (0–100 ng/ml) on the expression of extracellular matrix proteins and pro-inflammatory cytokines/chemokines were examined as well as the effects on rat cardiac fibroblast activities including proliferation, collagen gel contraction and migration. While IL-33 did not directly inhibit collagen I and collagen III production, it yielded a dose-dependent increase in the expression of interleukin-6 and monocyte chemotactic protein-1. Treatment of rat cardiac fibroblasts with IL-33 also impaired the migratory activity of these cells. Further experiments illustrated that IL-33 rapidly activated multiple signaling pathways including extracellular signal-regulated kinases, p38 mitogen-activated protein kinase, c-Jun N-terminal kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in a dose-dependent manner. Experiments were carried out with pharmacological inhibitors to determine the role of specific signaling pathways in the response of fibroblasts to IL-33. These experiments illustrated that the activation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinases are critical to the increased production of interleukin-6 and monocyte chemotactic protein-1 in response to IL-33. These studies suggest that IL-33 has an important role in the modulation of fibroblast function and gene expression. Surprisingly, IL-33 had no effect on the expression of genes encoding extracellular matrix components or on proliferation, markers typical of fibrosis. The major effects of IL-33 detected in these studies included inhibition of cell migration and activation of cytokine/chemokine expression. The previously reported inhibition of cardiac fibrosis may include more complicated mechanisms that involve other cardiac cell types. Future studies aimed at determining the effects of IL-33 on other cardiac cell types are warranted.