Mee John B, Antonopoulos Christos, Poole Stephen, Kupper Thomas S, Groves Richard W
Dermatology Section, Division of Medicine, Imperial College London, UK.
J Invest Dermatol. 2005 Jun;124(6):1267-74. doi: 10.1111/j.0022-202X.2005.23684.x.
Interleukin-1alpha (IL-1alpha) is a potent proinflammatory cytokine constitutively expressed by keratinocytes, which also synthesize a specific inhibitor of IL-1 activity, intracellular IL-1 receptor antagonist (IL-1ra). Although homeostatic regulation of the IL-1 system in keratinocytes has long been suspected, there is currently little evidence for this. To explore this issue, the PAM212 murine keratinocyte cell line was exposed to increasing concentrations of either IL-1alpha or IL-1ra and the opposing ligand was assessed by ELISA. Release of IL-1ra was induced following stimulation by murine IL-1alpha in a concentration-dependent manner and, conversely, IL-1ra stimulation increased IL-1alpha release. To determine whether a similar homeostatic circuit operates in vivo, epidermis from transgenic mice in which overexpression of IL-1alpha or IL-1ra was targeted to keratinocytes was analyzed. Epidermal sheets derived from IL-1alpha transgenic mice released eight times more IL-1ra than those from wild-type mice following ex vivo culture and similarly, IL-1alpha release was increased 3-4-fold in epidermal sheets derived from IL-1ra transgenic epidermis, Use of specific neutralizing antibodies against type I and type II IL-1 receptors indicated that the counter-regulation mechanism is mediated extracellularly through the type I IL-1 receptor alone. Taken together, these observations provide the first demonstration of mutual counter-regulation of IL-1 receptor ligands in keratinocytes.
白细胞介素-1α（IL-1α）是一种由角质形成细胞组成性表达的强效促炎细胞因子，角质形成细胞还合成IL-1活性的特异性抑制剂——细胞内IL-1受体拮抗剂（IL-1ra）。尽管长期以来人们一直怀疑角质形成细胞中IL-1系统的稳态调节，但目前对此几乎没有证据。为了探讨这个问题，将PAM212小鼠角质形成细胞系暴露于浓度不断增加的IL-1α或IL-1ra中，并通过酶联免疫吸附测定法评估其拮抗配体。小鼠IL-1α刺激后，IL-1ra的释放呈浓度依赖性诱导，相反，IL-1ra刺激增加了IL-1α的释放。为了确定体内是否存在类似的稳态回路，分析了IL-1α或IL-1ra过表达靶向角质形成细胞的转基因小鼠的表皮。离体培养后，来自IL-1α转基因小鼠的表皮片释放的IL-1ra比野生型小鼠的表皮片多八倍，同样，来自IL-1ra转基因表皮的表皮片中IL-1α的释放增加了3至4倍。使用针对I型和II型IL-1受体的特异性中和抗体表明，这种反调节机制仅通过I型IL-1受体在细胞外介导。综上所述，这些观察结果首次证明了角质形成细胞中IL-1受体配体的相互反调节作用。
