Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-5602, USA.
Eur J Immunol. 2013 Jul;43(7):1907-13. doi: 10.1002/eji.201243075. Epub 2013 May 13.
The complement activation product, C5a, is a key factor for regulation of inflammatory responses. C5a and C5adesArg bind to their receptors, C5aR and C5L2, but the functional roles of C5L2 remain controversial. We screened the patterns of 23 inflammatory mediators in cultures of LPS-activated mouse peritoneal elicited macrophages (PEMs) in the presence or absence of recombinant mouse C5a. Production of most mediators studied was suppressed by C5a, whereas G-CSF production was enhanced. G-CSF gene expression and secretion from PEMs was amplified two- to threefold by C5a in a dose- and time-dependent fashion. The degradation product C5adesArg promoted lower levels of G-CSF. The effects of C5a on G-CSF were associated with activation of PI3K/Akt and MEK1/2 signaling pathways. C5a did not enhance G-CSF production in cultures of PEMs from either C5aR- or C5L2-deficient mice, indicating that both C5a receptors are indispensable for mediating the effects of C5a in the production of G-CSF. Finally, G-CSF levels in plasma during polymicrobial sepsis after cecal ligation and puncture were substantially lower in C5aR- or C5L2-deficient mice as compared with that in C57BL/6J WT mice. These findings elucidate the functional characteristics of the C5L2 receptor during the acute inflammatory response.
补体激活产物 C5a 是调节炎症反应的关键因素。C5a 和 C5adesArg 与它们的受体 C5aR 和 C5L2 结合，但 C5L2 的功能作用仍存在争议。我们在 LPS 激活的小鼠腹腔渗出巨噬细胞（PEM）的培养物中筛选了 23 种炎症介质的模式，存在或不存在重组小鼠 C5a。研究中大多数介质的产生被 C5a 抑制，而 G-CSF 的产生则增强。G-CSF 基因表达和 PEM 分泌在 C5a 的剂量和时间依赖性方式下被放大两到三倍。降解产物 C5adesArg 促进了较低水平的 G-CSF。C5a 对 G-CSF 的影响与 PI3K/Akt 和 MEK1/2 信号通路的激活有关。C5a 没有增强 C5aR 或 C5L2 缺陷型小鼠 PEM 培养物中 G-CSF 的产生，表明 C5a 受体在介导 C5a 对 G-CSF 产生的作用中是不可或缺的。最后，在盲肠结扎和穿刺后的多微生物脓毒症期间，C5aR 或 C5L2 缺陷型小鼠血浆中的 G-CSF 水平明显低于 C57BL/6J WT 小鼠。这些发现阐明了 C5L2 受体在急性炎症反应中的功能特征。
