Interleukin-6 (IL-6) Trans Signaling Drives a STAT3-dependent Pathway That Leads to Hyperactive Transforming Growth Factor-β (TGF-β) Signaling Promoting SMAD3 Activation and Fibrosis via Gremlin Protein
Interleukin-6 (IL-6) Trans Signaling Drives a STAT3-dependent Pathway That Leads to Hyperactive Transforming Growth Factor-β (TGF-β) Signaling Promoting SMAD3 Activation and Fibrosis via Gremlin Protein
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DOI：
10.1074/jbc.m113.545822
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发表时间：
2014-04-04
影响因子：
4.8
通讯作者：
van Laar, Jacob M.
中科院分区：
文献类型：
--
作者：
O'Reilly, Steven;Ciechomska, Marzena;van Laar, Jacob M.
背景：IL-6是一种促纤维化分子，但其作用机制尚不清楚。结果：IL-6通过一种新的细胞因子Gremlin介导的STAT3和Smad3依赖的途径介导纤维化。结论：明确了IL-6介导的肝纤维化发生的新途径。意义：靶向Gremlin是STAT3下游纤维化的一个新的治疗靶点。纤维化是一种常见的、与各种病理相关的难治性疾病。其特征是大量细胞外基质分子积聚，主要包括I型胶原。IL-6是一种促纤维化细胞因子，在典型的纤维化自身免疫性系统性硬化症中升高，已知可诱导I型胶原表达，但其诱导机制(S)目前尚不清楚。利用体外培养的健康真皮成纤维细胞，我们分析了强调IL-6介导的胶原诱导的信号通路。我们发现，IL-6反式信号转导很重要，其作用依赖于STAT3；然而，这种作用是间接的，并通过增强的转化生长因子信号和经典的下游细胞介质SMAD3介导。这是由于骨形态发生蛋白(BMP)拮抗剂Gremlin-1的诱导，我们证明Gremlin-1是促纤维化的，并通过规范的转化生长因子信号介导。
Background: IL-6 is a profibrotic molecule, but the mechanism is unclear. Results: IL-6 mediates fibrosis via a STAT3- and Smad3-dependent pathway mediated via a novel cytokine, Gremlin. Conclusion: A novel pathway of IL-6 mediated fibrogenesis has been defined. Significance: Targeting Gremlin is a new therapeutic target in fibrosis downstream of STAT3.Fibrosis is a common and intractable condition associated with various pathologies. It is characterized by accumulation of an excessive amount of extracellular matrix molecules that primarily include collagen type I. IL-6 is a profibrotic cytokine that is elevated in the prototypic fibrotic autoimmune condition systemic sclerosis and is known to induce collagen I expression, but the mechanism(s) behind this induction are currently unknown. Using healthy dermal fibroblasts in vitro, we analyzed the signaling pathways that underscore the IL-6-mediated induction of collagen. We show that IL-6 trans signaling is important and that the effect is dependent on STAT3; however, the effect is indirect and mediated through enhanced TGF- signaling and the classic downstream cellular mediator Smad3. This is due to induction of the bone morphogenetic protein (BMP) antagonist Gremlin-1, and we show that Gremlin-1 is profibrotic and is mediated through canonical TGF- signaling.