%0 Journal Article
%T CRP and TNF- Induce PAPP-A Expression in Human Peripheral Blood Mononuclear Cells
%A Weiping Li
%A Hongwei Li
%A Fusheng Gu
%J Mediators of Inflammation
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/697832
%X Objective. The effects of C-reactive protein (CRP) and tumor necrosis factor-¦Á (TNF-¦Á) 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-¦Á 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-¦Á stimulation at only 2 and 8 hours, respectively. These findings indicate the dose-dependent effect of CRP and TNF-¦Á stimulation. Actinomycin D treatment completely prevented CRP and TNF-¦Á induction of PAPP-A mRNA and protein expression. Additionally, nuclear factor- (NF-) ¦ÊB inhibitor (BAY11-7082) potently inhibited both CRP and TNF-¦Á 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-¦Á through the NF-¦ÊB pathway. This mechanism may play a significant role in the observed increase of serum PAPP-A levels in acute coronary syndrome (ACS). 1. Introduction Pregnancy-associated plasma protein-A (PAPP-A) is a metzincin metalloproteinase primarily produced by the placental syncytiotrophoblast during pregnancy. PAPP-A is also synthesized by fibroblasts, osteoblasts, vascular smooth muscle cells (VSMCs), and endothelial cells (ECs). In vitro, PAPP-A functions to cleave insulin-like growth factor-binding protein 4 (IGFBP-4), an inhibitory IGFBP, consequently increasing IGF bioavailability for receptor activation [1¨C4]. In vivo, 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
%U http://www.hindawi.com/journals/mi/2012/697832/