Influence of troglitazone, sodium butyrate, 5-aminosalicylic acid and BAY 11-7082 on the chemokine ENA-78/CXCL5 secretion in the intestinal subepithelial myofibroblasts.

Crohnís disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) with a chronic relapsing and remitting course. Both of them have a similar etiology, but differ in location and degree of intestinal injury (1). The pathogenesis of inflammatory bowel disease is complex, involving environmental, genetic, microbial, immune factors and mucosal permeability abnormalities (2). It has been demonstrated that nuclear factor κB (NF-κB) plays a central role in the regulation of intracellular inflammatory signaling pathways in the large gut. NF-κB activates the expression of many genes associated with immune function in the gut, e.g., IL-8, IL-6, tumor necrosis factor-α (TNF-α), granulocyte/macrophage colony stimulating factor (GM-CSF), and epithelial neutrophil-activating peptide-78 (ENA-78/CXCL5). Chemokines IL8/CXCL8 and ENA-78/CXCL5 play complementary and sequential roles in neutrophil recruitment in the inflamed tissue in ulcerative colitis patients (3). NF-κB levels are increased in the intestinal lamina propria of patients with IBD. It was reported that a specific p65 antisense oligonucleotide can inhibit p65 expression and pro-inflammatory cytokine production by lamina propria macrophages in patients with active CD and UC. Although activation of NFκB does not occur in all patients with IBD, its perpetuated activation makes it a very attractive target for the therapeutic intervention in this disease (4). 5-Aminosalicylic acid (5-ASA) is one of the oldest anti-inflammatory agents used in the treatment of IBD, but the mechanism underlying its intestinal effects remains unknown. Recent data showing peroxisome proliferator-activated receptor gamma (PPAR-γ), is the major functional receptor mediating the common aminosalicylate activities in IBD have also reinforced the role of this receptor in the control of intestinal inflammation (5). PPAR-γ ligands inhibit NF-κB signaling pathway. High levels of PPAR-γ expression have been reported in colonic tissues in epithelial cells (3). PPAR-γ binds several different groups of drugs such as thiazolidinediones, also known as glitazones. Troglitazone (Tro) was the first glitazone developed for therapeutic use in patients with diabetes (6). Activation of PPAR-γ provides the protection against experimental IBD (7). Short-chain fatty acid enriched diet is recommended for IBD patients. One of these acids ñ butyric acid has been recognized as histone deacetylase inhibitor. According to Quivy et al. (8) deacetylation and acetylation processes are implicated in the regulation of NF-κB transcriptional activity. Fundamental biological processes such as cell motility, proliferation, differentiation, apoptosis, morphogenesis, tissue repair, inflammation, and the immune response in gut are controlled by myofibroblasts. Intestinal subepithelial myofibroblasts (ISEMF) are located in the lamina propria under the epithelial cell layer (9). The present study was aimed at evaluating ENA-78/CXCL5 secretion by human normal colon myofibroblasts CCD-18Co treated