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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >The ceramide-1-phosphate analogue PCERA-1 modulates tumour necrosis factor-alpha and interleukin-10 production in macrophages via the cAMP-PKA-CREB pathway in a GTP-dependent manner.
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The ceramide-1-phosphate analogue PCERA-1 modulates tumour necrosis factor-alpha and interleukin-10 production in macrophages via the cAMP-PKA-CREB pathway in a GTP-dependent manner.

机译：1磷酸神经酰胺类似物PCERA-1通过cAMP-PKA-CREB途径以GTP依赖性方式调节巨噬细胞中的肿瘤坏死因子-α和白介素10的产生。

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摘要

The synthetic phospho-ceramide analogue-1 (PCERA-1) down-regulates production of the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) and up-regulates production of the anti-inflammatory cytokine interleukin-10 (IL-10) in lipopolysaccharide (LPS) -stimulated macrophages. We have previously reported that PCERA-1 increases cyclic adenosine monophosphate (cAMP) levels. The objective of this study was to delineate the signalling pathway leading from PCERA-1 via cAMP to modulation of TNF-alpha and IL-10 production. We show here that PCERA-1 elevates intra-cellular cAMP level in a guanosine triphosphate-dependent manner in RAW264.7 macrophages. The cell-permeable dibutyryl cAMP was able to mimic the effects of PCERA-1 on cytokine production, whereas 8-chloro-phenylthio-methyladenosine-cAMP, which specifically activates the exchange protein directly activated by cAMP (EPAC) but not protein kinase A (PKA), failed to mimic PCERA-1 activities. Consistently, the PKA inhibitor H89 efficiently blocked PCERA-1-driven cytokine modulation as well as PCERA-1-stimulated phosphorylation of cAMP response element binding protein (CREB) on Ser-133. Finally, PCERA-1 activated cAMP-responsive transcription of a luciferase reporter, in synergism with the phosphodiesterase (PDE)-4 inhibitor rolipram. Our results suggest that PCERA-1 activates a G(s) protein-coupled receptor, leading to elevation of cAMP, which acts via the PKA-CREB pathway to promote TNF-alpha suppression and IL-10 induction in LPS-stimulated macrophages. Identification of the PCERA-1 receptor is expected to set up a new target for development of novel anti-inflammatory drugs.
机译：合成的磷酸神经酰胺类似物1（PCERA-1）下调促炎性细胞因子肿瘤坏死因子-α（TNF-alpha）的产生，并上调抗炎性细胞因子白介素10（IL- 10）在脂多糖（LPS）刺激的巨噬细胞中。我们以前曾报道过PCERA-1可增加环磷酸腺苷（cAMP）的水平。这项研究的目的是描绘从PCERA-1经由cAMP介导的TNF-α和IL-10产生调节的信号通路。我们在这里显示PCERA-1在RAW264.7巨噬细胞中以鸟苷三磷酸依赖性方式提高细胞内cAMP水平。具有细胞渗透性的二丁酰基cAMP能够模仿PCERA-1对细胞因子产生的影响，而8-氯-苯硫基-甲基腺苷cAMP可以特异性激活cAMP直接激活的交换蛋白（EPAC），而不激活蛋白激酶A（ PKA），无法模仿PCERA-1活动。一致地，PKA抑制剂H89有效地阻断了PCERA-1驱动的细胞因子的调控，以及PCERA-1刺激的Ser-133上cAMP反应元件结合蛋白（CREB）的磷酸化。最后，PCERA-1与磷酸二酯酶（PDE）-4抑制剂rolipram协同作用，激活了萤光素酶报道分子的cAMP响应转录。我们的研究结果表明PCERA-1激活一个G（s）蛋白偶联受体，导致cAMP升高，它通过PKA-CREB途径在LPS刺激的巨噬细胞中促进TNF-α抑制和IL-10诱导。鉴定PCERA-1受体有望为开发新型抗炎药建立新的靶标。

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