Lipopolysaccharide-induced gene expression in murine peritoneal macrophages is selectively suppressed by agents that elevate intracellular cAMP.
Lipopolysaccharide-induced gene expression in murine peritoneal macrophages is selectively suppressed by agents that elevate intracellular cAMP.
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DOI：
10.4049/jimmunol.142.4.1274
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发表时间：
1989-02
影响因子：
4.4
通讯作者：
C. Tannenbaum;Thomas A. Hamilton
中科院分区：
文献类型：
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作者：
C. Tannenbaum;Thomas A. Hamilton
细胞内cAMP的升高与巨噬细胞活化的抑制有关。本研究已经检查了改变细胞内cAMP水平的药剂对LPS诱导的巨噬细胞基因表达的影响。用微量LPS处理小鼠腹腔巨噬细胞导致多种mRNA的表达显著增强，包括在血小板衍生生长因子刺激的成纤维细胞中首次观察到的感受态基因JE和KC，以及编码炎性单核因子IL-1和TNF的基因。如果在用LPS刺激前15分钟首先用霍乱毒素或双丁酰cAMP处理巨噬细胞，则编码JE和TNF的mRNA的积累被强烈抑制，而KC和IL-1的mRNA水平不受影响。JE和TNF mRNA水平的抑制是剂量依赖性的，在10至500 μ M的二丁酰cAMP的范围内;浓度高达1 mM不影响KC或IL-1的表达。当在LPS处理开始后向巨噬细胞中加入二丁酰cAMP时，抑制作用以时间依赖性方式减弱。此外，二丁酰cAMP抑制LPS诱导的TNF基因的转录激活。以前的工作表明，LPS诱导的JE表达似乎是由多磷酸肌醇水解介导的，涉及转录后机制。用二丁酰cAMP处理抑制用佛波酯和A23187处理诱导的JE表达，这表明基因表达的抑制必须作用于除初始跨膜信号传导事件之外的位点。最后，二丁酰cAMP仅轻微影响JE基因的组成型转录，表明抑制可能涉及转录后机制。这些结果表明，诱导早期蛋白和炎症单核因子的基因编码的表达选择性调节细胞内cAMP的升高。这种效应可能是多效性的，涉及多种分子机制。
Elevation of intracellular cAMP has been associated with the suppression of macrophage activation. The present study has examined the effects of agents that alter intracellular levels of cAMP on LPS-induced macrophage gene expression. Treatment of murine peritoneal macrophages with trace amounts of LPS leads to dramatically enhanced expression of multiple mRNA including the competence genes JE and KC, first observed in platelet-derived growth factor-stimulated fibroblasts, and those encoding the inflammatory monokines IL-1 and TNF. If macrophages are first treated with cholera toxin or dibutyryl cAMP 15 min before stimulation with LPS, the accumulation of mRNA encoding both JE and TNF is strongly suppressed whereas mRNA levels for KC and IL-1 are unaffected. The suppression of JE and TNF mRNA levels is dose dependent, in the range of 10 to 500 microM dibutyryl cAMP; concentrations as high as 1 mM do not affect the expression of either KC or IL-1. When dibutyryl cAMP is added to macrophages after initiation of LPS treatment, suppressive effects are diminished in a time-dependent fashion. Furthermore, dibutyryl cAMP suppresses the LPS-induced transcriptional activation of the TNF gene. Previous work has shown that the LPS-induced expression of JE appears to be mediated by hydrolysis of polyphosphoinositides and involves a post-transcriptional mechanism. Treatment with dibutyryl cAMP suppresses JE expression induced by treatment with phorbol ester and A23187 suggesting that inhibition of gene expression must act at a site other than the initial transmembrane signaling event. Finally, dibutyryl cAMP only marginally affects the constitutive transcription of the JE gene indicating that suppression may involve a post-transcriptional mechanism. These results indicate that expression of genes encoding inducible early proteins and inflammatory monokines are selectively regulated by elevation of intracellular cAMP. Such effects may be pleiotropic in nature involving multiple molecular mechanisms.