MyD88-dependent production of IL-17F is modulated by the anaphylatoxin C5a via the Akt signaling pathway
MyD88-dependent production of IL-17F is modulated by the anaphylatoxin C5a via the Akt signaling pathway
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DOI：
10.1096/fj.11-191205
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发表时间：
2011-12-01
期刊：
影响因子：
4.8
通讯作者：
Ward, Peter A.
中科院分区：
文献类型：
--
作者：
Bosmann, Markus;Patel, Vinay R.;Ward, Peter A.
白细胞介素-17 （IL-17）家族细胞因子在先天免疫防御细菌和真菌病原体中发挥重要作用。虽然对IL-17A的了解很多，但对IL-17F异构体的信息却少得多。在这里，我们研究了IL-17F的基因表达和释放及其在补体系统中的调控。LPS激活TLR4后，小鼠腹腔巨噬细胞产生IL-17F，并在12小时后达到峰值。这种作用完全依赖于接头蛋白MyD88的存在。补体激活产物C5a （EC50 = 10 nM）的存在通过受体C5aR扩增了IL-17F的产生。体外信号研究表明，LPS或C5a，或两者结合，可导致Akt在苏氨酸308位点磷酸化，而在丝氨酸473位点不发生磷酸化。用PI3K-Akt药物抑制剂处理巨噬细胞可显著降低IL-17F的产生以及IL-17F mRNA的表达。在内毒素血症中，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。在内毒素血症中，体内IL-17F的充分产生需要C5a。在盲肠结扎和穿刺脓毒症模型中发现了类似的结果。这些数据表明，IL-17F的最大生产需要补体激活和C5a的存在。- bossmann， M, Patel， V. R, Russkamp， N. F, Pache， F, Zetoune， F. S, Sarma， J. V, Ward， P. a。过敏毒素C5a通过Akt信号通路调节myd88依赖性IL-17F的产生。中华医学杂志，25,4222-4232（2011）。www.fasebj.org
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 (EC50 = 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.-Bosmann, M., Patel, V. R., Russkamp, N. F., Pache, F., Zetoune, F. S., Sarma, J. V., Ward, P. A. MyD88-dependent production of IL-17F is modulated by the anaphylatoxin C5a via the Akt signaling pathway. FASEB J. 25, 4222-4232 (2011). www.fasebj.org