Department of Pathology, The University of Michigan Medical School, 1301 Catherine Rd., Ann Arbor, MI 48109-5602, USA.
FASEB J. 2011 Dec;25(12):4222-32. doi: 10.1096/fj.11-191205. Epub 2011 Aug 22.
The interleukin-17 (IL-17) family of cytokines plays important roles in innate immune defenses against bacterial and fungal pathogens. While much is known about IL-17A, much less information is available about the IL-17F isoform. Here, we investigated gene expression and release of IL-17F and its regulation by the complement system. IL-17F was produced in mouse peritoneal elicited macrophages after TLR4 activation by LPS, peaking after 12 h. This effect was completely dependent on the presence of the adaptor protein MyD88. The copresence of the complement activation product, C5a (EC(50)=10 nM), amplified IL-17F production via the receptor C5aR. In vitro signaling studies indicated that LPS or C5a, or the combination, caused phosphorylation of Akt occurring at threonine 308 but not at serine 473. Treatment of macrophages with pharmacologic inhibitors of PI3K-Akt greatly reduced production of IL-17F as well as mRNA for IL-17F. In endotoxemia, C5a levels peaked at 6 h, while IL-17F levels peaked between 6-12 h. Full in vivo production of IL-17F during endotoxemia required C5a. A similar result was found in the cecal ligation and puncture sepsis model. These data suggest that maximal production of IL-17F requires complement activation and presence of C5a.
白细胞介素-17 (IL-17) 细胞因子家族在针对细菌和真菌病原体的先天免疫防御中发挥重要作用。虽然人们对 IL-17A 了解很多，但关于 IL-17F 同工型的信息却很少。在这里，我们研究了 IL-17F 的基因表达和释放及其受补体系统调节的情况。TLR4 激活后，LPS 可诱导小鼠腹腔渗出巨噬细胞产生 IL-17F，12 小时达到高峰。这种效应完全依赖于衔接蛋白 MyD88 的存在。补体激活产物 C5a（EC(50)=10 nM）的共存通过受体 C5aR 放大了 IL-17F 的产生。体外信号转导研究表明，LPS 或 C5a，或两者的组合，导致 Akt 的丝氨酸 308 磷酸化，但不导致丝氨酸 473 磷酸化。PI3K-Akt 的药理学抑制剂处理巨噬细胞可大大降低 IL-17F 的产生以及 IL-17F 的 mRNA。内毒素血症中，C5a 水平在 6 小时达到峰值，而 IL-17F 水平在 6-12 小时达到峰值。内毒素血症期间，IL-17F 的完全体内产生需要 C5a。在盲肠结扎和穿刺脓毒症模型中也发现了类似的结果。这些数据表明，IL-17F 的最大产生需要补体激活和 C5a 的存在。
