Takahashi Nozomi, Vanlaere Ineke, de Rycke Riet, Cauwels Anje, Joosten Leo A B, Lubberts Erik, van den Berg Wim B, Libert Claude
Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, Netherlands.
J Exp Med. 2008 Aug 4;205(8):1755-61. doi: 10.1084/jem.20080588. Epub 2008 Jul 28.
Tumor necrosis factor (TNF) has very potent antitumor activity, but it also provokes a systemic inflammatory response syndrome that leads to shock, organ failure, and death. Here, we demonstrate that interleukin (IL)-17, a proinflammatory cytokine known to be produced mainly by activated T cells, has a critical role in this process. Antiserum against IL-17 or deletion of Il17r protected mice against a lethal TNF challenge. Serum levels of TNF-induced IL-6 and nitric oxide metabolites were significantly reduced in mice deficient in the IL-17R. TNF-induced leukocyte influx in the small intestine was reduced, and there was no injury to the small intestine. Surprisingly, electron microscopy showed that IL-17 was constitutively present in Paneth cells of the crypts. Upon TNF challenge, the intracellular pool of IL-17 in these cells was drastically reduced, suggesting rapid release of IL-17 from the granules of Paneth cells. Our findings assign a novel role for IL-17 in an acute inflammation and identify Paneth cells as a source of the IL-17 that plays a role in this process. These data indicate that innate immune cytokine responses in the local mucosa may participate in rapidly amplifying responses to systemic inflammatory challenges.
肿瘤坏死因子（TNF）具有很强的抗肿瘤活性，但它也会引发全身炎症反应综合征，进而导致休克、器官衰竭和死亡。在此，我们证明白细胞介素（IL）-17，一种已知主要由活化T细胞产生的促炎细胞因子，在这一过程中起关键作用。抗IL-17抗血清或Il17r基因缺失可保护小鼠免受致命的TNF攻击。在IL-17R缺陷的小鼠中，TNF诱导的IL-6和一氧化氮代谢产物的血清水平显著降低。TNF诱导的小肠白细胞流入减少，小肠未出现损伤。令人惊讶的是，电子显微镜显示IL-17在隐窝的潘氏细胞中持续存在。在TNF攻击后，这些细胞中IL-17的细胞内池急剧减少，表明IL-17从潘氏细胞的颗粒中快速释放。我们的研究结果赋予了IL-17在急性炎症中的新作用，并确定潘氏细胞是在此过程中发挥作用的IL-17的来源。这些数据表明，局部黏膜中的固有免疫细胞因子反应可能参与对全身炎症挑战的快速放大反应。
