Pregnancy-Associated Plasma Protein A Induces Inflammatory Cytokine Expression by Activating IGF-I/PI3K/Akt Pathways.

Weiping Li,Li Zhou,Hongwei Li,Zijian Wang,Bing Hua

doi:10.1155/2019/8436985

Abstract

Pregnancy-associated plasma protein A (PAPP-A) was previously reported to be an inflammatory biomarker and a prognostic marker of acute coronary syndrome (ACS) and involved in the process of atherosclerosis and plaque rupture. However, the role of PAPP-A in inflammation is poorly understood. In this study, we aimed to investigate the role of PAPP-A in macrophage activation and inflammatory cytokine production. RAW264.7 macrophages were treated with or without PAPP-A. Reverse-transcriptase quantitative real-time PCR (RT-qPCR) and Western blot were performed to detect gene and protein expressions. The concentration of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in culture supernatants was determined by ELISA. Results showed that PAPP-A significantly stimulated the expression of MCP-1, TNF-α, and IL-6 at both transcriptional and translational levels in a dose-dependent and time-dependent manner. The secretion of these inflammatory cytokines by macrophages was also increased after PAPP-A treatment. Moreover, PAPP-A activated the IGF-I/PI3K/Akt signaling pathway in macrophages. The PAPP-A-mediated upregulation of MCP-1, TNF-α, and IL-6 mRNA and protein levels were strongly inhibited by PI3K inhibitors or IGF-IR siRNA, indicating that the upregulation of MCP-1, TNF-α, and IL-6 could involve the IGF-I/PI3K/Akt pathway. Together, this study demonstrates that PAPP-A activates the macrophage signaling pathway (IGF-I/PI3K/Akt), which drives the expression and production of inflammatory cytokines known to contribute to the initiation and progression of ACS. These findings indicate that PAPP-A may play a proinflammatory role in the pathophysiology of ACS and serve as a potential therapeutic target.

Highlights

Atherosclerosis, a complex inflammatory response to chronic endothelial injury, involves several cell types and multiple cytokines, growth factors, and enzymes [1]
We first examined the effect of Pregnancy-associated plasma protein A (PAPP-A) on the expression of monocyte chemoattractant protein-1 (MCP-1), TNFα, and IL-6 in RAW264.7 macrophages by Reversetranscriptase quantitative real-time PCR (RT-qPCR) and Western blot assays
The protein expressions of tumor necrosis factor-α (TNF-α) and IL-6 were significantly increased by PAPP-A at 6 h, while that of MCP-1 was increased at 12 h

Summary

Introduction

Atherosclerosis, a complex inflammatory response to chronic endothelial injury, involves several cell types and multiple cytokines, growth factors, and enzymes [1]. Increasing evidences support a central role of inflammation in atherosclerosis progression and complication and acute coronary syndrome (ACS) development. The characteristic components of atherosclerotic plaque are macrophages, which can produce various chemokines, proinflammatory cytokines, and inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). Macrophages may contribute to atherosclerosis development and ACS pathogenesis. In 2001, Conover et al first reported that PAPP-A was abundantly expressed in coronary plaque cells and the extracellular matrix of ruptured and eroded unstable plaques from patients who died from sudden cardiac causes. PAPP-A has been detected in ruptured and eroded

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