MEK1/2 inhibitors induce interleukin-5 expression in mouse macrophages and lymphocytes

• Published in: Biochemical and biophysical research communications 2016-05, Vol.473 (4), p.939-946
• Main Authors: Li, Xiaoju, Cao, Xingyue, Zhang, Xiaomeng, Kang, Yanhua, Zhang, Wenwen, Yu, Miao, Ma, Chuanrui, Han, Jihong, Duan, Yajun, Chen, Yuanli
• Format: Article
• Language: English
• Subjects: Animals; Atherosclerosis; Butadienes - pharmacology; Cell Line; Flavonoids - pharmacology; Interleukin-5; Interleukin-5 - biosynthesis; Interleukin-5 - genetics; Interleukin-5 - metabolism; Lymphocytes - drug effects; Lymphocytes - enzymology; Lymphocytes - immunology; Macrophage; Macrophages - drug effects; Macrophages - enzymology; Macrophages - immunology; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 2 - antagonists & inhibitors; MEK1/2 inhibitor; Mice; Mice, Inbred C57BL; Nitriles - pharmacology; oxLDL; Protein Kinase Inhibitors - pharmacology; Protein Stability - drug effects
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.03.156

Uptake of oxidized low-density lipoprotein (oxLDL) by macrophages facilitates the formation of foam cells, the prominent part of atherosclerotic lesions. Interleukin-5 (IL-5) is a cytokine regulating interactions between immune cells. It also activates the production of T15/EO6 IgM antibodies in B-1 cells, which can bind oxLDL thereby demonstrating anti-atherogenic properties. We previously reported that inhibition of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by mitogen-activated protein kinase kinases 1/2 (MEK1/2) inhibitors can reduce atherosclerosis. In this study, we determined the effects of MEK1/2 inhibitors on IL-5 production both in vitro and in vivo. In vitro, MEK1/2 inhibitors (PD98059 and U0126) substantially inhibited phosphorylation of MEK1/2 and ERK1/2. Associated with inhibition of ERK1/2 phosphorylation both in vitro and in vivo, MEK1/2 inhibitors induced IL-5 protein expression in macrophages (RAW macrophages and peritoneal macrophages) and lymphocytes (EL-4 cells). In vivo, administration of mice with MEK1/2 inhibitors increased serum IL-5 levels, and IL-5 protein expression in mouse spleen and liver. At the mechanistic level, we determined that MEK1/2 inhibitors activated IL-5 mRNA expression and IL-5 promoter activity in the liver X receptor (LXR) dependent manner indicating the induction of IL-5 transcription. In addition, we determined that MEK1/2 inhibitors enhanced IL-5 protein stability. Taken together, our study demonstrates that MEK1/2 inhibitors induce IL-5 production which suggests another anti-atherogenic mechanism of MEK1/2 inhibitors. •MEK1/2 inhibitors activate IL-5 production both in vitro and in vivo.•MEK1/2 inhibitors induce IL-5 expression by activating IL-5 transcription and enhancing IL-5 protein stability.•Induction of IL-5 production may make contribution to the anti-atherogenic properties of MEK1/2 inhibitors.