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MEK1/2 Inhibitors Induce interleukin-5 Expression in Mouse Macrophages and Lymphocytes

MEK1/2 Inhibitors Induce interleukin-5 Expression in Mouse Macrophages and Lymphocytes

Xiaoju Li, Xingyue Cao, Xiaomeng Zhang, Yanhua Kang, Wenwen Zhang, Miao Yu, Chuanrui Ma, Jihong Han, Yajun Duan, Yuanli Chen

Biochem Biophys Res Commun. 2016 May 13;473(4):939-946.

PMID: 27045084

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248599	Interleukin-5 from mouse			Price

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