CRP and TNF-α Induce PAPP-A Expression in Human Peripheral Blood Mononuclear Cells

Weiping Li,Fusheng Gu,Hongwei Li

doi:10.1155/2012/697832

Abstract

Objective. The effects of C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) on pregnancy-associated plasma protein-A (PAPP-A) expression in human peripheral blood mononuclear cells (PBMCs) require further investigation. Methods. The PAPP-A levels in culture supernatants, PAPP-A mRNA expression, and cellular PAPP-A expression were measured in human PBMCs isolated from fresh blood donations provided by 6 healthy volunteers (4 donations per volunteer). Analyses were conducted by ultrasensitive ELISA, western blotting, and RT-PCR following stimulation with CRP or TNF-α cytokines. Results. PAPP-A mRNA and protein levels after CRP stimulation peaked at 24 hours, whereas peak PAPP-A mRNA and protein levels were achieved after TNF-α stimulation at only 2 and 8 hours, respectively. These findings indicate the dose-dependent effect of CRP and TNF-α stimulation. Actinomycin D treatment completely prevented CRP and TNF-α induction of PAPP-A mRNA and protein expression. Additionally, nuclear factor- (NF-) κB inhibitor (BAY11-7082) potently inhibited both CRP and TNF-α stimulated PAPP-A mRNA and protein expression. Conclusions. Human PBMCs are capable of expressing PAPP-A in vitro, expression that may be regulated by CRP and TNF-α through the NF-κB pathway. This mechanism may play a significant role in the observed increase of serum PAPP-A levels in acute coronary syndrome (ACS).

Highlights

Pregnancy-associated plasma protein-A (PAPP-A) is a metzincin metalloproteinase primarily produced by the placental syncytiotrophoblast during pregnancy
The current study investigates the ability of C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) to induce PAPP-A expression in the peripheral blood mononuclear cells (PBMCs) of healthy volunteers
The current study indicates that PAPP-A expression in human PBMCs may be regulated by CRP and TNF-α through the nuclear factor- (NF-)κB pathway, a mechanism that may play a critical role in increases in serum PAPPA levels during acute coronary syndrome (ACS)

Summary

Introduction

Pregnancy-associated plasma protein-A (PAPP-A) is a metzincin metalloproteinase primarily produced by the placental syncytiotrophoblast during pregnancy. PAPP-A is synthesized by fibroblasts, osteoblasts, vascular smooth muscle cells (VSMCs), and endothelial cells (ECs). Several studies have shown a similar role for PAPP-A in modulating site- and event-specific IGF signaling during injury repair processes [2]. Recent studies have indicated that PAPP-A is a novel biomarker for plaque instability and inflammation useful in early diagnosis, risk stratification, and prognostic prediction in patients with acute coronary syndrome (ACS) [5, 6]. PAPP-A was found abundantly expressed in ruptured and eroded human atherosclerotic plaques, colocalized with activated smooth muscle cells and macrophages [7, 8]. Since plaque-derived PAPP-A is being considered as a new biomarker that may potentially play a role in the development of atherosclerotic lesions [9, 10]. A better understanding of its cellular source and regulation is important to the future development and implementation of therapeutics utilizing this biomarker

Methods

Results

Conclusion