Immunology Letters 121 (2008) 22–26 Contents lists available at ScienceDirect Immunology Letters journal homepage: www.elsevier.com/locate/ Serum amyloid A induces CCL20 secretion in mononuclear cells through MAPK (p38 and ERK1/2) signaling pathways Silvana Sandri a,∗ , Elaine Hatanaka b,c , Andressa G. Franco a , Alziana M.C. Pedrosa a , Hugo P. Monteiro d , Ana Campa a a Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo CEP 05508-900, Brazil b Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil c Área de Ciências Biológicas e da Saúde, Universidade Cruzeiro do Sul, São Paulo, Brazil d Departamento de Bioquímica, Universidade Federal de São Paulo, São Paulo, Brazil article info Article history: Received 26 May 2008 Received in revised form 14 July 2008 Accepted 21 July 2008 Available online 19 August 2008 Keywords: CCL20 Mononuclear cells and serum amyloid A (SAA) abstract Although the serum levels of SAA had been reported to be upregulated during inflammatory/infectious process, the role of this acute-phase protein has not been completely elucidated. In previous studies, we demonstrated that SAA stimulated the production of TNF-, IL-1, IL-8, NO, and ROS by neutrophils and/or mononuclear cells. Herein we demonstrate that SAA induces the expression and release of CCL20 from cultured human blood mononuclear cells. We also focus on the signaling pathways triggered by SAA. In THP-1 cells SAA promotes phosphorylation of p38 and ERK1/2. Furthermore, the addition of SB203580 (p38 inhibitor) and PD98059 (ERK 1/2 inhibitor) inhibits the expression and release of CCL20 in mononu- clear cells treated with SAA. Our results point to SAA as an important link of innate to adaptive immunity, once it might act on the recruitment of mononuclear cells. © 2008 Elsevier B.V. All rights reserved. 1. Introduction In mammals, the acute-phase response is a systemic reaction to inflammation/infection and tissue injury that protects the host, minimizing tissue damage, and promoting healing [1,2]. A char- acteristic of the acute-phase response is the rapid increase in production of acute-phase proteins (APPs), including C-reactive protein (CRP), serum amyloid A (SAA) and others [3]. Secretion of these APPs by hepatocytes results in a marked increase (up to 1000-fold for SAA; higher for CRP) in their plasma concentrations above the basal level, reaching as much as 80 M or 1 mg/mL for SAA [3,4]. Like other APPs, the production of SAA is usually trig- gered by inflammatory cytokines and secreted mainly by activated macrophages and monocytes, and also by endothelial cells, lym- phocytes and other cells [2]. However, little is known about the precise role of SAA in inflammation and immunity. In previous studies, we had demonstrated immunomodulatory activities of SAA in human leukocytes, such as the induction of expression and release of tumoral necrosis factor-alpha (TNF-), interleukin-1beta (IL-1), interleukin-8 (IL-8), the priming activ- ity for opsonized particles [5–8]. Recently, we showed that SAA is an inducer of the nitric oxide (NO) production in macrophages ∗ Corresponding author. Tel.: +55 11 3091 3741; fax: +55 11 3813 2197. E-mail address: ssandri@usp.br (S. Sandri). and that it might be an endogenous agonist for the TLR4 complex [9]. These and other effects of SAA on leukocyte migration, adhe- sion, and calcium mobilization make SAA an important mediator of the inflammatory process [10]. Furthermore, SAA is triggered in chronic conditions such as diabetes [11]. In that case the basal SAA serum levels are persistently elevated and are probably an important factor for the maintenance of a proinflammatory status contributing to the development of further diabetic complications [11]. The chemokine system coordinates leukocyte migration in immunity and inflammation, and is also implicated in the patho- genesis of many diseases. Among the arrangements of chemokines, CCL20, also known as macrophage inflammatory protein-3 alpha (MIP-3) or LARC, has been linked to a variety of diseases, includ- ing cancer [12], rheumatoid arthritis [13], and periodontal diseases [14]. It attracts memory T and natural killer cells to sites of inflam- mation and immature dendritic cells [15]. CC chemokine receptor 6 (CCR6) is the only known receptor for CCL20 and it, in turn, is bound only this chemokine [16]. CCL20 has been shown to be expressed predominantly in lymph nodes, appendix, fetal liver, fetal lung and several cell lines (for review [17]). The expression of CCL20 is strongly upregulated by inflammatory signals and down regulated by the anti-inflammatory cytokine IL-10 [18]. Herein, our attention focuses on the description of the effect of SAA on the expression and release of CCL20 by mononuclear cells and the signaling pathway involved in this induction. 0165-2478/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.imlet.2008.07.013