白细胞介素-17可刺激人类巨噬细胞产生和表达促炎细胞因子白细胞介素-β和肿瘤坏死因子-α。

IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages.

作者信息

Jovanovic D V, Di Battista J A, Martel-Pelletier J, Jolicoeur F C, He Y, Zhang M, Mineau F, Pelletier J P

机构信息

Osteoarthritis Research Unit, Centre de recherche L.-C. Simard, University of Montreal, Quebec, Canada.

出版信息

J Immunol. 1998 Apr 1;160(7):3513-21.

PMID:9531313

Abstract

IL-17 is a newly described, T cell-derived cytokine with ill-defined physiologic properties. As such, we examined the release of proinflammatory mediators by human macrophages in response to recombinant human (rh) IL-17. IL-1beta and TNF-alpha expression and synthesis were up-regulated by rhIL-17 in a dose (ED50 was 50 +/- 9 ng/ml)- and time-dependent fashion, with cytokine accumulation reaching a zenith after 9 h. Release of IL-6, PGE2, IL-10, IL-12, IL-1R antagonist, and stromelysin was also stimulated by rhIL-17. IL-1beta and TNF-alpha mRNA expression levels were controlled by rhIL-17 in a complex manner with an initial 30-min inhibitory phase, and then up-regulation beginning at 1 h and reaching a plateau at about 3 h. The latter expression pattern closely mirrored the nuclear accumulation of the transcription factor nuclear factor-kappaB. cAMP mimetics isobutyl-1-methylxanthine (IBMX), forskolin, PGE2, and cholera toxin reversed rhIL-17-induced release of TNF-alpha, but had no consistent effect on induced IL-1beta synthesis. Induced release of TNF-alpha was also inhibited by serine/threonine protein kinase inhibitors KT-5720 (protein kinase A) and Calphostin C (protein kinase C), mitogen-activated protein kinase kinase inhibitor PD098059, and a nonspecific tyrosine kinase inhibitor, genistein. Calphostin C alone abrogated the rhIL-17-induced release of IL-1beta. The antiinflammatory cytokines IL-4 (p < 0.01) and IL-10 (p < 0.02) completely reversed rhIL-17-stimulated IL-1beta release, while IL-13 and TGF-beta2 were partially effective (59 and 43% diminution, respectively). IL-10 exerted a significant suppressive effect on IL-17-induced TNF-alpha release (99%, p < 0.02), while the inhibitory effects of IL-4, IL-13, and TGF-beta2 on TNF-alpha secretion were partial (48, 10, and 23%, respectively). The data suggest a pivotal role for IL-17 in initiating and/or sustaining an inflammatory response.

摘要

白细胞介素-17（IL-17）是一种新发现的、由T细胞产生的细胞因子，其生理特性尚不明确。因此，我们检测了重组人（rh）IL-17刺激下人巨噬细胞促炎介质的释放情况。rhIL-17以剂量（半数有效剂量为50±9 ng/ml）和时间依赖性方式上调白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的表达及合成，细胞因子积累在9小时后达到峰值。rhIL-17还刺激了IL-6、前列腺素E2（PGE2）、IL-10、IL-12、IL-1受体拮抗剂和基质溶解素的释放。rhIL-17以复杂的方式控制IL-1β和TNF-α mRNA表达水平，最初有30分钟的抑制期，然后在1小时开始上调，约3小时达到平台期。后一种表达模式与转录因子核因子-κB的核内积累密切相关。环磷酸腺苷（cAMP）模拟物异丁基-1-甲基黄嘌呤（IBMX）、福斯可林、PGE2和霍乱毒素可逆转rhIL-17诱导的TNF-α释放，但对诱导的IL-1β合成没有一致的影响。丝氨酸/苏氨酸蛋白激酶抑制剂KT-5720（蛋白激酶A）、钙泊三醇（蛋白激酶C）、丝裂原活化蛋白激酶激酶抑制剂PD098059和一种非特异性酪氨酸激酶抑制剂染料木黄酮也可抑制诱导的TNF-α释放。单独使用钙泊三醇可消除rhIL-17诱导的IL-1β释放。抗炎细胞因子IL-4（p<0.01）和IL-10（p<0.02）可完全逆转rhIL-17刺激的IL-1β释放，而IL-13和转化生长因子-β2（TGF-β2）部分有效（分别减少59%和43%）。IL-10对IL-17诱导的TNF-α释放有显著抑制作用（99%，p<0.02），而IL-4、IL-13和TGF-β2对TNF-α分泌的抑制作用是部分性的（分别为48%、10%和23%）。这些数据表明IL-17在启动和/或维持炎症反应中起关键作用。