Mxi1-0 regulates the growth of human umbilical vein endothelial cells through extracellular signal-regulated kinase 1/2 (ERK1/2) and interleukin-8 (IL-8)-dependent pathways

Weiling Wu; Zhenzhen Hu; Feng Wang; Hao Gu; Xiuqin Jiang; Jinjin Xu; Xi Zhan; Datong Zheng; Zhengdong Zhang

doi:10.1371/journal.pone.0178831

Mxi1-0 regulates the growth of human umbilical vein endothelial cells through extracellular signal-regulated kinase 1/2 (ERK1/2) and interleukin-8 (IL-8)-dependent pathways

PLoS One. 2017 Jun 2;12(6):e0178831. doi: 10.1371/journal.pone.0178831. eCollection 2017.

Authors

Weiling Wu¹, Zhenzhen Hu², Feng Wang¹, Hao Gu³, Xiuqin Jiang², Jinjin Xu², Xi Zhan⁴, Datong Zheng^{1

2

3}, Zhengdong Zhang⁵

Affiliations

¹ Children's Health Center, The Second Hospital, Nanjing Medical University, Nanjing, Jiangsu, P. R. China.
² Clinical Molecular Diagnostic Laboratory, The Second Hospital, Nanjing Medical University, Nanjing, Jiangsu, P. R. China.
³ The Second Clinical School, Nanjing Medical University, Nanjing, Jiangsu, P. R.China.
⁴ Center for Vascular and inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, United States of America.
⁵ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, P. R.China.

Abstract

Mxi1 plays an important role in the regulation of cell proliferation. Mxi1-0, a Mxi1 isoform, has a different N-terminal amino acid sequence, intracellular location and expression profile from Mxi1. However, the precise role of Mxi1-0 in cell proliferation and the molecular mechanism underlying its function remain poorly understood. Here, we showed that Mxi1-0 suppression decreased the proliferation of human umbilical vein endothelial cells (HUVECs) along with cell accumulation in the G2/M phase. Mxi1-0 suppression also significantly decreased the expression and secretion of interleukin (IL-8). Neutralizing IL-8 in conditioned medium (CM) from Mxi1-0-overexpressed HUVECs significantly eliminated CM-induced proliferation of HUVECs. In addition, Mxi1-0 suppression significantly decreased the activity of MAP kinase ERK1/2. Treatment of HUVECs with U0126, an ERK1/2 signaling inhibitor, attenuated autocrine production of IL-8 induced by Mxi1-0 overexpression. On the other hand, Mxi1-0 overexpression-induced IL-8 increased the level of phosphorylated ERK1/2 in HUVECs, and such increasing was diminished in cells incubated with CM, which neutralized with anti-IL-8 antibody. Taken together, our results suggest that Mxi1-0 regulates the growth of HUVECs via the IL-8 and ERK1/2 pathways, which apparently reciprocally activate each other.

MeSH terms

Basic Helix-Loop-Helix Transcription Factors / physiology*
Endothelium, Vascular / cytology
Endothelium, Vascular / enzymology
Human Umbilical Vein Endothelial Cells
Humans
Interleukin-8 / metabolism*
MAP Kinase Signaling System*
Phosphorylation
Tumor Suppressor Proteins / physiology*
Umbilical Veins / cytology
Umbilical Veins / enzymology

Substances

Basic Helix-Loop-Helix Transcription Factors
Interleukin-8
MXI1 protein, human
Tumor Suppressor Proteins

Grants and funding

This work was supported by research grants from State Key Laboratory of Reproductive Medicine, Nanjing Medical University (SKLRM-KF-1202) to Weiling Wu, the National Natural Science Foundation of China (81301822) and the Research Program funded by Nanjing Medical University (2012NJMU088) to Zhenzhen Hu, Key Project supported by Medical Science and technology development Foundation, Nanjing Department of Health (YKK13177) to Datong Zheng. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.