Fatty acid-binding protein regulates LPS-induced TNF-a production in mast cells Noriko Yamamoto a,b,1 , Izumi Kaneko c,1 , Keiju Motohashi a,e , Hiroyuki Sakagami d , Yasuhiro Adachi a , Nobuko Tokuda a , Tomoo Sawada a , Hiroshi Furukawa c , Yoshiya Ueyama b , Kohji Fukunaga e , Masao Ono c , Hisatake Kondo d , Yuji Owada a,Ã a Department of Organ Anatomy, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube 755-8505, Japan b Department of Oral and Maxillofacial Surgery, Yamaguchi University Graduate School of Medicine, Japan c Department of Pathology, Tohoku University Graduate School of Medicine, Japan d Department of Histology, Tohoku University Graduate School of Medicine, Japan e Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Science, Japan article info Article history: Received 22 February 2008 Received in revised form 30 May 2008 Accepted 28 June 2008 abstract There has been increasing evidence for the involvement of fatty acid-binding proteins (FABPs) in the cytokine production of macrophages and dendritic cells probably through the control of cellular lipid metabolism and signal transduction. Since mast cells (MCs) are recently shown to be involved in immune response through modification of cytokine production, it is possible that some FABPs could also be involved in the immune response of MCs. In this study, we found that epidermal-type FABP (E-FABP) was expressed in murine bone marrow-derived MCs (BMMCs). Using BMMCs from genetically E-FABP-null mutated mice, we demonstrated that E-FABP in BMMCs plays a key role in the production of TNF-a following lipopolysaccharide (LPS) stimulation. In the in vivo septic peritonitis model (cecal ligation and puncture model), E-FABP-null mice showed a significantly increased mortality compared to wild-type mice. However, no significant difference in antigen-induced cytokine production was observed between wild-type and E-FABP-null BMMCs, and systemic anaphylaxis was equally induced in vivo in both wild-type and E-FABP-null mice. These results suggest that E-FABP is specifically involved in the LPS-induced cytokine production of MCs, and could play a role in the host-defense against bacterial infection, possibly through regulation of TNF-a production. & 2008 Elsevier Ltd. All rights reserved. 1. Introduction Mast cells (MCs) induce profound allergic responses through release of a variety of inflammatory mediators, including histamine and a number of immuno-regulatory cytokines, by cross-linking high-affinity receptors for IgE (FceRI) on their plasma membrane and appropriate antigens [1,2]. In contrast to the harmful role of MCs, recent studies have revealed that MCs that reside in high numbers at the host–environment interface play a protective role in the host defense against bacteria [3,4]. When MCs are exposed to lipopolysaccharide (LPS), a bacterial cell wall component from gram-negative bacteria, they produce proinflammatory cytokines such as TNF-a and IL-6 through activation of toll-like receptors (TLRs) on their cell surface [5,6]. This cytokine response of MCs to various pathogens is strictly regulated by the cellular chemical environments including eicosanoids such as leukotrienes (LTs) and prostaglandins (PGs) [7–10], derivatives from long-chain fatty acids (LCFA). Thus, LCFAs are supposed to directly modulate the inflammatory response through modulation of intracellular signal transduction pathways of MCs [11]. However, the molecular mechanism underlying such regulation by LCFAs is still poorly understood. Due to the hydrophobic property of LCFAs, intracellular transport or storage of LCFAs requires an interaction with carrier proteins such as fatty acid-binding proteins (FABPs) [12]. FABPs constitute a multigene family of structurally homologous cyto- solic proteins capable of binding LCFAs and various eicosanoids, and could work as vehicles of water-insoluble ligands. Recent evidence suggests that the FABP family of proteins could play a role in (i) prompting cellular flux of poorly water-soluble ligands and their subsequent metabolic utilization or transformation, (ii) sequestration of ligands that limits their association with alternative-binding sites in the cell, and (iii) transport of ligands in ARTICLE IN PRESS Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/plefa Prostaglandins, Leukotrienes and Essential Fatty Acids 0952-3278/$ - see front matter & 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2008.06.003 Ã Corresponding author. Tel.: +81836 22 2201; fax: +81836 22 2203. E-mail address: yowada@yamaguchi-u.ac.jp (Y. Owada). 1 N.Y. and I.K. contributed equally to this work. Prostaglandins, Leukotrienes and Essential Fatty Acids 79 (2008) 21–26