title: MEK1/2 inhibitors induce interleukin-5 expression in mouse macrophages and lymphocytes.
abstract: 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.
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xingyue
authors.initials: X
authors.lastname: Cao
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Medicine, Hangzhou Normal University, Hangzhou, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Kang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Chuanrui
authors.initials: C
authors.lastname: Ma
authors.affiliation: College of Medical Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
authors.affiliation: College of Medical Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, Nankai University, Tianjin, China. Electronic address: yajunduan@nankai.edu.cn.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Duan
authors.affiliation: College of Medical Engineering, Hefei University of Technology, Hefei, China; School of Medicine, Nankai University, Tianjin, China. Electronic address: yuanli2014@nankai.edu.cn.
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D005419:Flavonoids / Q000494:pharmacology; D015848:Interleukin-5 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects
chemical_list: D002070:Butadienes; D005419:Flavonoids; D015848:Interleukin-5; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482129:Map2k2 protein, mouse; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Atherosclerosis; Interleukin-5; MEK1/2 inhibitor; Macrophage; oxLDL