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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation
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Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation

机译：2型白介素1受体的角质形成细胞表达介导白介素1介导的炎症的局部和特异性抑制

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Epidermal keratinocytes can express two types of interleukin 1 (IL-1) receptors: IL-1R1, which is active in signal transduction, and the less well characterized IL-1R2, which is incapable of transducing a signal and can be shed from cells. The binding of IL-1 in solution by IL-1R2 has been demonstrated, and it has been proposed to inhibit IL-1-mediated responses through this mechanism. We and others have reported that keratinocytes can be induced to express IL-1R2 both in vitro and in vivo, often under conditions that also favor IL-1 gene expression. We hypothesized that production of IL-1R2 by keratinocytes would be an efficient means to achieve local inhibition of IL-1-mediated responses without systemic consequences. To test this hypothesis, we have generated transgenic mice that constitutively express IL-1R2 on basal keratinocytes. Keratinocytes cultured from these animals shed the soluble form of the receptor into culture supernatants, and IL-1-inducible production of granulocyte/macrophage colony-stimulating factor was markedly inhibited. In vivo, acute cutaneous vascular leakage, as well as chronic inflammation induced by a well characterized IL-1-dependent stimulus, was significantly inhibited in IL-1R2 transgenic animals. In contrast, contact hypersensitivity was unaffected, suggesting that overexpression of IL-1R2 did not inhibit all types of inflammation globally. Finally, systemic injection of IL-1 induced equivalent levels of plasma IL-6 in IL-1R2 transgenic and nontransgenic mice, suggesting that the activity of the transgenic IL-1R2 remained predominantly local and did not influence systemic IL-1 responses. We conclude that tissue-specific production of IL-1R2 can mediate IL-1 antagonism in tissue microenvironments without systemic consequences. Our transgenic mice may be a useful tool for determining the degree to which different types of cutaneous inflammation depend on the IL-1 system.
机译：表皮角质形成细胞可以表达两种类型的白介素1（IL-1）受体：IL-1R1和IL-1R2，IL-1R1在信号转导中有效，IL-1R2不能转导信号，可以从细胞中脱落。已经证明了IL-1R2与溶液中的IL-1结合，并且已经提出通过这种机制抑制IL-1介导的应答。我们和其他人已报道，通常在也有利于IL-1基因表达的条件下，可诱导角质形成细胞在体外和体内表达IL-1R2。我们假设角质形成细胞产生IL-1R2将是实现局部抑制IL-1介导的反应而没有系统性后果的有效手段。为了检验该假设，我们已经产生了在基础角质形成细胞上组成性表达IL-1R2的转基因小鼠。从这些动物培养的角质形成细胞将受体的可溶性形式释放到培养上清液中，并且IL-1诱导的粒细胞/巨噬细胞集落刺激因子的产生受到明显抑制。在体内，急性的皮肤血管渗漏以及由特征明确的IL-1依赖性刺激引起的慢性炎症在IL-1R2转基因动物中得到显着抑制。相反，接触性超敏反应不受影响，表明IL-1R2的过表达并不能完全抑制所有类型的炎症。最后，在IL-1R2转基因和非转基因小鼠中，系统性注射IL-1诱导血浆IL-6的水平相等，这表明转基因IL-1R2的活性主要保持局部状态，并且不影响系统性IL-1反应。我们得出结论，IL-1R2的组织特异性产生可以介导组织微环境中的IL-1拮抗作用，而没有系统性后果。我们的转基因小鼠可能是确定不同类型的皮肤炎症取决于IL-1系统的程度的有用工具。

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