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Effects of interleukin-33 on cardiac fibroblast gene expression and activity

机译：白细胞介素33对心脏成纤维细胞基因表达和活性的影响

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摘要

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.
机译：白介素33（IL-33）是白介素1（IL-1）家族的最新成员。它是由多种细胞类型产生的，以响应各种压力，包括出血和机械负荷增加。尽管只是相对较新的发现，但IL-33已显示参与多种病理过程，包括促进2型T辅助细胞相关的自身免疫性疾病。相反，还发现IL-33在心血管疾病中具有保护作用。最近的研究表明，IL-33可减轻小鼠心血管负荷增加引起的心脏纤维化（经主动脉缩窄）。由于心脏纤维化很大程度上取决于心脏成纤维细胞增加的细胞外基质产生，因此我们假设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的调节的作用和功能，以检验该假设。在分离的成年大鼠心脏成纤维细胞的mRNA和蛋白水平检测到IL-33受体白细胞介素1受体样1（ST2）的表达。随后，检查了IL-33处理（0-100。ng / ml）对细胞外基质蛋白和促炎性细胞因子/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）的影响和迁移。尽管IL-33不能直接抑制I型胶原和III型胶原的产生，但白介素6和单核细胞趋化蛋白1的表达却呈剂量依赖性增加。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迅速激活了多种信号通路，包括细胞外信号调节激酶，p38丝裂原激活的蛋白激酶，c-Jun N端激酶和激活的B细胞核因子κ轻链增强剂（NF- kB）呈剂量依赖性。使用药理抑制剂进行了实验，以确定特定信号通路在成纤维细胞对IL-33的反应中的作用。这些实验说明，p38促分裂原活化蛋白激酶和细胞外信号调节激酶的激活对于响应IL-33的白介素6和单核细胞趋化蛋白1的增加产量至关重要。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。出人意料的是，IL-33对编码细胞外基质成分的基因的表达或对纤维化的典型标志物增殖没有影响。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/趋化因子的表达。先前报道的对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。将来有必要进行旨在确定IL-33对其他心脏细胞类型的影响的研究。

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