Gene expression in mononuclear cells from patients with inflammatory bowel disease $ Elizabeth E. Mannick, a,b, * Joseph C. Bonomolo, b Ronald Horswell, a Jennifer J. Lentz, a Maria-Stella Serrano, b Adriana Zapata-Velandia, a,b Mariella Gastanaduy, a,b Jessica L. Himel, a,b Steven L. Rose, c John N. Udall, Jr., b Conrad A. Hornick, d and Zhiyun Liu b a Stanley S. Scott Cancer Center, New Orleans, LA 70112, USA b Louisiana State University Inflammatory Bowel Disease Center of Excellence, New Orleans, LA 70112, USA c Department of Physiology, Louisiana State University, New Orleans, LA 70112, USA d Prometheus Laboratories, San Diego, CA 92121-4203, USA Received 19 December 2003; accepted with revision 17 March 2004 Available online 4 June 2004 Abstract Objectives. Discovery of Nod2 as the inflammatory bowel disease 1 (IBD1) susceptibility gene has brought to light the significance of mononuclear cells in inflammatory bowel disease pathogenesis. The purpose of this study was to examine changes in gene expression in peripheral blood mononuclear cells in patients with untreated Crohn’s disease (CD) and ulcerative colitis (UC) as compared to patients with other inflammatory gastrointestinal disorders and to healthy controls. Methods. We used a 2400 gene cDNA glass slide array (MICROMAXk) to examine gene expression in peripheral blood mononuclear cells from seven patients with Crohn’s disease, five patients with ulcerative colitis, 10 patients with other inflammatory gastrointestinal disorders, and 22 age- and sex-matched controls. Results. Novel categories of genes differentially expressed in Crohn’s disease and ulcerative colitis patients included genes regulating hematopoietic cell differentiation and leukemogenesis, lipid raft-associated signaling, the actin cytoskeleton, and vesicular trafficking. Conclusions. Altered gene expression in mononuclear cells may contribute to inflammatory bowel disease pathogenesis. D 2004 Published by Elsevier Inc. Keywords: Crohn’s disease; Microarray; Mononuclear cell Introduction Inflammatory bowel disease (IBD), comprising ulcera- tive colitis (UC) and Crohn’s disease (CD), has been treated clinically for over 70 years, but the underlying cause and a definitive cure have yet to be found. IBD is thought to result from a complex interaction between environmental varia- bles including microbial and dietary antigens, and polygenic genetic susceptibility. In the last 10 years, a global effort involving linkage disequilibrium mapping and positional cloning studies of multiply affected families with inflam- matory bowel disease has uncovered a growing number of susceptibility loci on chromosomes 1, 3, 4, 5, 10, 12, 16, 17, 22, and X [1–8]. The first IBD susceptibility gene to be identified, Nod2, encodes an intracellular receptor for peptidoglycan, a com- ponent of bacterial cells walls. The downstream targets of Nod2 are RIP kinase and NF-kappa B. Three distinct poly- morphisms in Nod2 (R702W, G908R, and 1007fs) are found with increased frequency in a subset of patients with CD and result in defective activation of NF kappa B in monocytes, intestinal epithelial cells, and Paneth cells ex- posed to peptidoglycan and lipopolysaccharide [9–11]. The discovery that Nod2, a protein primarily expressed in mononuclear cells, could contribute to organ-specific disease placed mononuclear cells and innate immunity at the center of IBD pathogenesis for the first time. Recently, the Runx1 gene has been identified as a susceptibility gene for rheumatoid arthritis [12]. Runx 1 is a gene primarily expressed in hematopoietic cells that, when 1521-6616/$ - see front matter D 2004 Published by Elsevier Inc. doi:10.1016/j.clim.2004.03.014 $ Supplementary data associated with this article can be found, in the online version, at doi:10.1016/S1521-6616(04)00104-4. * Corresponding author. Louisiana State University Inflammatory Bowel Disease Center of Excellence, 533 Bolivar Street, Room 409, New Orleans, LA 70112. Fax: +1-504-568-6888. E-mail address: emanni@lsuhsc.edu (E.E. Mannick). www.elsevier.com/locate/yclim Clinical Immunology 112 (2004) 247 – 257