Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-α responses
Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-α responses
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DOI：
10.1073/pnas.122041599
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发表时间：
2002-05-28
影响因子：
11.1
通讯作者：
Conti, M
中科院分区：
文献类型：
--
作者：
Jin, SLC;Conti, M
脂多糖（LPS）刺激先天免疫反应需要激活信号级联反应，最终导致促炎细胞因子的合成和分泌。鉴于磷酸二酯酶（PDE）抑制剂对LPS诱导的细胞因子产生的抑制作用，我们研究了PDE 4（4型cAMP特异性PDE）-B和PDE 4 D缺陷小鼠的LPS反应。LPS刺激小鼠外周血白细胞可诱导PDE 4 B mRNA的积累，并增加PDE 4的活性。这种反应在PDE 4 B缺陷但不是PDE 4D缺陷的小鼠中完全不存在。LPS诱导循环白细胞分泌肿瘤坏死因子-α在PDE 4 B缺陷小鼠中减少约90%，但在PDE 4D缺陷小鼠中没有减少。无论用于刺激的LPS剂量如何，受损的LPS反应都是明显的，并且与肿瘤坏死因子-α mRNA积累减少90%以上相关。对LPS的反应性降低也存在于其他炎性细胞中，包括腹膜和肺巨噬细胞。这些发现表明，LPS激活PDE 4 B基因构成了有效免疫应答所必需的反馈调节。
Lipopolysaccharide (LPS) stimulation of the innate immune response requires the activation of signaling cascades that culminate in the synthesis and secretion of proinflammatory cytokines. Given the inhibitory effects of phosphodiesterase (PDE) inhibitors on LPS-induced cytokine production, we have investigated LPS responses in mice deficient in PDE4 (type 4 cAMP-specific PDE)-B and PDE4D. LPs stimulation of mouse peripheral leukocytes induced PDE4B mRNA accumulation and increased PDE4 activity. This response was completely absent in mice deficient in PDE4B but not PDE4D. LPS induction of tumor necrosis factor-alpha secretion by circulating leukocytes was decreased by approximately 90% in mice deficient in PDE4B but not in mice lacking PDE4D. The impaired LPS response was evident regardless of the LPS dose used for stimulation and was associated with a more than 90% decrease in tumor necrosis factor-alpha mRNA accumulation. A decreased responsiveness to LPS was also present in other inflammatory cells, including peritoneal and lung macrophages. These findings demonstrate that PDE4B gene activation by LPS constitutes a feedback regulation essential for an efficient immune response.