Attenuation of TNF production and experimentally induced inflammation by PDE4 inhibitor rolipram is mediated by MAPK phosphatase-1
Attenuation of TNF production and experimentally induced inflammation by PDE4 inhibitor rolipram is mediated by MAPK phosphatase-1
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DOI：
10.1111/bph.12189
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发表时间：
2013-08-01
影响因子：
7.3
通讯作者：
Moilanen, Eeva
中科院分区：
文献类型：
--
作者：
Korhonen, Riku;Hommo, Tuija;Moilanen, Eeva
背景与目的3',5'-环核苷酸PDE4在多种炎症和免疫细胞中表达，PDE4催化cAMP水解为5' amp，下调细胞中cAMP信号传导。MAPK磷酸酶-1 （MKP-1）是内源性p38 MAPK信号抑制因子，限制炎症基因表达和炎症。在本研究中，我们研究了PDE4抑制剂罗利普兰对MKP-1表达的影响，以及MKP-1是否参与了罗利普兰的抗炎作用。实验方法研究罗利普兰对J774小鼠巨噬细胞系及野生型（WT）和MKP-1（-/-）小鼠原代腹腔巨噬细胞（PM）产生TNF的影响。我们还研究了罗利普兰对卡拉胶诱导的WT和MKP-1（-/-）小鼠足部炎症的影响。关键结果：罗利普兰、非选择性PDE抑制剂IBMX和cAMP类似物8-Br-cAMP在J774细胞和PM中增强smkp -1的表达。罗利普兰增强MKP-1 mRNA的表达可被PKA抑制剂逆转。罗利普兰、IBMX和8-Br-cAMP也能抑制活化巨噬细胞中TNF的产生。因此，罗利普兰抑制WT小鼠的pm中TNF的产生，但有趣的是，在MKP-1（-/-）小鼠的pm中没有。此外，罗利普兰减轻了角叉菜胶诱导的WT小鼠足部炎症，但在MKP-1（-/-）小鼠中没有。结论和意义spde4抑制剂罗利普兰可增强MKP-1的表达，MKP-1至少部分介导PDE4抑制的抗炎作用。结果表明，增强MKP-1表达和/或MKP-1活性的化合物具有作为新型抗炎药的潜力。
BACKGROUND AND PURPOSE3',5'-Cyclic nucleotide PDE4 is expressed in several inflammatory and immune cells, and PDE4 catalyses the hydrolysis of cAMP to 5'AMP, down-regulating cAMP signalling in cells. MAPK phosphatase-1 (MKP-1) is an endogenous p38 MAPK signalling suppressor and limits inflammatory gene expression and inflammation. In the present study, we investigated the effect of a PDE4 inhibitor rolipram on MKP-1 expression and whether MKP-1 is involved in the anti-inflammatory effects of rolipram.EXPERIMENTAL APPROACHThe effect of rolipram on TNF production was investigated in J774 mouse macrophage cell line and in primary mouse peritoneal macrophages (PM) from wild-type (WT) and MKP-1(-/-) mice. We also investigated the effect of rolipram on carrageenan-induced paw inflammation in WT and MKP-1(-/-) mice.KEY RESULTSMKP-1 expression was enhanced by rolipram, by a non-selective PDE inhibitor IBMX and by a cAMP analogue 8-Br-cAMP in J774 cells and in PM. Enhanced MKP-1 mRNA expression by rolipram was reversed by a PKA inhibitor. Rolipram, IBMX and 8-Br-cAMP also inhibited TNF production in activated macrophages. Accordingly, rolipram inhibited TNF production in PMs from WT mice but, interestingly, not in PMs from MKP-1(-/-) mice. Furthermore, rolipram attenuated carrageenan-induced paw inflammation in WT but not in MKP-1(-/-) mice.CONCLUSIONS AND IMPLICATIONSPDE4 inhibitor rolipram was found to enhance the expression of MKP-1, and MKP-1 mediated, at least partly, the anti-inflammatory effects of PDE4 inhibition. The results suggest that compounds that enhance MKP-1 expression and/or MKP-1 activity hold potential as novel anti-inflammatory drugs.