IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: Evidence for enhanced cutaneous immunity
IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: Evidence for enhanced cutaneous immunity
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DOI：
10.4049/jimmunol.170.11.5438
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发表时间：
2003-06-01
影响因子：
4.4
通讯作者：
Stingl, G
中科院分区：
文献类型：
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作者：
Kopp, T;Lenz, P;Stingl, G
p40是促炎细胞因子IL-12和IL-23的共同亚基，由驻留的皮肤细胞产生。尽管IL-12的体内作用已得到充分证实，但对IL-23在皮肤免疫应答中的作用知之甚少。在这项研究中，我们表明，p40转基因TG小鼠组成型产生IL-23（p19/p40），但不是IL-12（p35/p40），在基础角质形成细胞的共分泌TG p40与内源性p19。在同窝（LM）小鼠中重复注射rIL-23导致与p40 TG小鼠相似的炎性皮肤病，证实了IL-23的促炎活性。此外，p40 TG角质形成细胞分泌IL-23诱导朗格汉斯细胞（LC）数量增加，共刺激分子显著上调，表明与LM LC相比，角蛋白14（K14）/p40 LC成熟提前。在功能水平上，新鲜分离的K14/p40 LC在刺激同种异体T细胞增殖的能力上大大超过了来自LM动物的LC。为了评估IL-23是否在体内调节皮肤免疫应答，我们使用同种异体皮肤移植模型。与来自非TG LM（H-2（q））的皮肤移植物（平均存活时间：10.7天，p < 0.01）相比，来自K14/p40供体（H-2（q））的全层皮肤移植物穿过MHC I类和II类屏障移植到BALB/c（H-2（d））受体上以显著加速的方式（平均存活时间：8.8天）被排斥。基于这些结果，我们建议，IL-23诱导的LC的变化可能是一个重要的机制，在指导皮肤免疫反应的结果。
p40, the common subunit of the proinflammatory cytokines IL-12 and IL-23, is produced by resident skin cells. Whereas the in vivo effects of IL-12 are well established, little is known about the role of IL-23 in cutaneous immune responses. In this study we show that p40 transgenic TG mice constitutively produce IL-23 (p19/p40), but not IL-12 (p35/p40), in basal keratinocytes by cosecretion of TG p40 with endogenous p19. Repeated injections of rIL-23 in littermate (LM) mice result in an inflammatory skin disease similar to that of p40 TG mice, confirming the proinflammatory activity of IL-23. Furthermore, IL-23 secretion by p40 TG keratinocytes induces elevated numbers of Langerhans cells (LC) with a marked up-regulation of costimulatory molecules, indicating advanced maturation of keratin 14 (K14)/p40 LC when compared with LM LC. At the functional level, freshly isolated K14/p40 LC greatly exceeded LC from LM animals in their capacity to stimulate allogeneic T cell proliferation. To assess whether IL-23 regulates cutaneous immune responses in vivo, we used an allogeneic skin transplantation model. Full thickness skin grafts from K14/p40 donors (H-2(q)) transplanted across a MHC class I and class II barrier onto BALB/c (H-2(d)) recipients were rejected in a significantly accelerated fashion (mean survival time: 8.8 days) when compared with skin grafts from non-TG LM (H-2(q)) (mean survival time: 10.7 days,p < 0.01). Based on these results we propose that IL-23-induced changes of LC may be an important mechanism in directing the outcome of cutaneous immune responses.