Interleukin-1β Induces Hyaluronan and CD44-Dependent Cell Protrusions That Facilitate Fibroblast-Monocyte Binding
Interleukin-1β Induces Hyaluronan and CD44-Dependent Cell Protrusions That Facilitate Fibroblast-Monocyte Binding
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DOI：
10.1016/j.ajpath.2013.02.038
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发表时间：
2013-06-01
影响因子：
6
通讯作者：
Phillips, Aled
中科院分区：
文献类型：
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作者：
Meran, Soma;Martin, John;Phillips, Aled
持续性炎症是进行性组织纤维化的一个众所周知的决定因素;然而，这一过程的机制仍不清楚。越来越多的证据表明细胞因子IL-1 β在促纤维化反应中的作用。我们以前证明，用IL-1 β刺激的成纤维细胞增加了多糖透明质酸（HA）的产生，并增加了HA合酶（HAS-2）的表达。本研究的目的是确定IL-1 β诱导的HA和HAS-2生成变化的意义。在这项研究中，我们发现用IL-1 β刺激成纤维细胞导致与细胞相关的HA重新定位到细胞外膜，在那里它形成HAS 2和CD 44依赖性细胞膜突起。CD 44集中在膜突起内，在那里它与细胞内粘附分子1共定位。此外，我们已经确定这些细胞突起通过MAPK/ERK信号传导增强IL-1 β依赖性成纤维细胞-单核细胞结合。尽管先前的数据已经表明HA结合蛋白TSG-6在维持转化生长因子β 1依赖性HA外壳中的重要性，但TSG-6对于IL-1 β依赖性HA突起的形成不是必需的，因此将其鉴定为IL-1 β和转化生长因子β 1依赖性HA基质之间的关键差异。总之，这些数据表明，IL-1 β依赖性HA的产生在成纤维细胞免疫活化中起作用，导致单核细胞在发炎组织内的隔离，并为永久性炎症提供可能的机制。
Persistent inflammation is a well-known determinant of progressive tissue fibrosis; however, the mechanisms underlying this process remain unclear. There is growing evidence indicating a role of the cytokine IL-1 beta in profibrotic responses. We previously demonstrated that fibroblasts stimulated with IL-1 beta increased their generation of the polysaccharide hyaluronan (HA) and increased their expression of the HA synthase enzyme (HAS-2). The aim of this study was to determine the significance of IL-1 beta- induced changes in HA and HAS-2 generation. In this study, we found that stimulation of fibroblasts with IL-1 beta results in the relocalization of HA associated with the cell to the outer cell membrane, where it forms HAS2- and CD44-dependent cell membrane protrusions. CD44 is concentrated within the membrane protrusions, where it co-localizes with the intracellular adhesion molecule 1. Furthermore, we have identified that these cell protrusions enhance IL-1 beta-dependent fibroblast-monocyte binding through MAPK/ERK signaling. Although previous data have indicated the importance of the HA-binding protein TSG-6 in maintaining the transforming growth factor beta 1-dependent HA coat, TSG-6 was not essential for the formation of the IL-1 beta-dependent HA protrusions, thus identifying it as a key difference between IL-1 beta- and transforming growth factor beta 1-dependent HA matrices. In summary, these data suggest that IL-1 beta-dependent HA generation plays a role in fibroblast immune activation, leading to sequestration of monocytes within inflamed tissue and providing a possible mechanism for perpetual inflammation.