Hömmö Tuija, Pesu Marko, Moilanen Eeva, Korhonen Riku
The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland.
Immunoregulation, BioMediTech, University of Tampere, Tampere, Finland.
Basic Clin Pharmacol Toxicol. 2015 Aug;117(2):96-104. doi: 10.1111/bcpt.12380. Epub 2015 Feb 25.
Mitogen-activated protein kinases (MAPKs) include p38 MAPKs, c-Jun N-terminal kinases (JNKs) and Extracellular signal-regulated kinases (ERKs), and they regulate many cell processes, such as cell division, differentiation and release of inflammatory mediators. MAPK activity is controlled by mitogen-activated protein kinase phosphatases (MKPs), a phosphatase family with 11 members. MKP-1 is the most studied member of MKP family, and it is one of the anti-inflammatory factors induced by glucocorticoids. Less is known about the other MAPK phosphatases although they hold a promise as anti-inflammatory drug targets. In this study, we investigated the effect of MKP-5 on MAPK phosphorylation and cytokine production in J774 mouse macrophages. We used MKP-5 siRNA and an MKP-5 inhibitor (AS077234-4) to modulate MKP-5 function. We found that MKP-5 controlled p38 MAPK phosphorylation, but not that of JNK or ERK. In addition, the production of IL-6 and TNF was suppressed by MKP-5 in macrophages. Our results introduce a novel concept that compounds able to enhance MKP-5 expression and/or activity hold anti-inflammatory potential, because MKP-5 down-regulates the release of inflammatory mediators by controlling p38 MAPK activity.
丝裂原活化蛋白激酶（MAPKs）包括p38 MAPKs、c-Jun氨基末端激酶（JNKs）和细胞外信号调节激酶（ERKs），它们调节许多细胞过程，如细胞分裂、分化和炎症介质的释放。MAPK活性受丝裂原活化蛋白激酶磷酸酶（MKPs）控制，MKPs是一个有11个成员的磷酸酶家族。MKP-1是MKP家族中研究最多的成员，它是糖皮质激素诱导的抗炎因子之一。尽管其他MAPK磷酸酶有望成为抗炎药物靶点，但人们对它们的了解较少。在本研究中，我们研究了MKP-5对J774小鼠巨噬细胞中MAPK磷酸化和细胞因子产生的影响。我们使用MKP-5 siRNA和MKP-5抑制剂（AS077234-4）来调节MKP-5的功能。我们发现MKP-5控制p38 MAPK的磷酸化，但不控制JNK或ERK的磷酸化。此外，MKP-5在巨噬细胞中抑制IL-6和TNF 的产生。我们的结果引入了一个新概念，即能够增强MKP-5表达和/或活性的化合物具有抗炎潜力，因为MKP-5通过控制p38 MAPK活性来下调炎症介质的释放。
