IL-15 functions as a potent autocrine regulator of macrophage proinflammatory cytokine production: evidence for differential receptor subunit utilization associated with stimulation or inhibition.
IL-15 functions as a potent autocrine regulator of macrophage proinflammatory cytokine production: evidence for differential receptor subunit utilization associated with stimulation or inhibition.
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DOI：
10.4049/jimmunol.159.6.2941
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发表时间：
1997-09
影响因子：
4.4
通讯作者：
D. Alleva;S. B. Kaser;M. A. Monroy;M. Fenton;D. Beller
中科院分区：
文献类型：
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作者：
D. Alleva;S. B. Kaser;M. A. Monroy;M. Fenton;D. Beller
细胞因子IL-15似乎通过利用IL-2 R复合物的一部分来模拟IL-2对淋巴细胞的刺激活性。虽然以前没有报道IL-15对Mphi活性的影响，但其来源于活化的Mphi，表明在调节Mphi功能中可能具有自分泌作用，并促使我们确定IL-15是否调节LPS活化的Mphi细胞因子的产生。而高IL-15浓度增强促炎性（即，TNF-α、IL-1和IL-6）和抗炎（即，IL-10）的细胞因子产生抑制2 - 6倍，极低的IL-15浓度（皮摩尔至阿托摩尔范围）显著地和选择性地抑制Mphi促炎性细胞因子产生，但不抑制抗炎性细胞因子产生2 - 4倍。IL-15刺激（而非抑制）TNF-α产生需要（IL-2/IL-15）受体β链，如受体亚基阻断研究和缺乏IL-2 R β缺陷小鼠Mphi刺激所示。相反，抑制最有可能涉及α受体（IL-15 R α），因为这种高亲和力受体将被低浓度的IL-15所吸引，并且其诱导表达以时间和LPS剂量依赖性方式与抑制程度相关。此外，Ab介导的中和研究显示，内源性IL-15活性调节Mphi活化，其动力学与外源性添加IL-15的反应相似：抑制剂活性随时间增加，与IL-15 R α基因表达相关。本研究证实了IL-15在Mphi调节中的新的剂量依赖性和自分泌活性。
The cytokine IL-15 appears to mimic the stimulatory activity of IL-2 on lymphocytes by utilizing part of the IL-2R complex. Although effects of IL-15 on Mphi activities have not previously been reported, its derivation from activated Mphi suggested a possible autocrine role in regulating Mphi functions and prompted us to determine whether IL-15 modulated LPS-activated Mphi cytokine production. Whereas high IL-15 concentrations enhanced proinflammatory (i.e., TNF-alpha, IL-1, and IL-6) and anti-inflammatory (i.e., IL-10) cytokine production by two- to sixfold, extremely low IL-15 concentrations (picomolar to attomolar range) markedly and selectively suppressed Mphi proinflammatory, but not anti-inflammatory, cytokine production by two- to fourfold. The stimulation (but not the suppression) of TNF-alpha production by IL-15 required the (IL-2/IL-15) receptor beta chain, as demonstrated by receptor subunit-blocking studies and lack of stimulation of Mphi from IL-2Rbeta-deficient mice. Conversely, suppression most likely involved the alpha receptor (IL-15R alpha) because this high affinity receptor would be engaged by low concentrations of IL-15, and its inducible expression correlated with the degree of suppression in both a time- and LPS dose-dependent fashion. Moreover, Ab-mediated neutralization studies revealed that endogenous IL-15 activity regulated Mphi activation with kinetics similar to that seen in response to exogenously added IL-15: suppressor activity increased over time in correlation with IL-15R alpha gene expression. This study demonstrates a novel dose-dependent and autocrine activity of IL-15 in Mphi regulation.