Simvastatin inhibits NF-κB signaling in intestinal epithelial cells and ameliorates acute murine colitis

Abstract

Statins, HMG-CoA reductase inhibitors exert pleiotropic anti-inflammatory properties in vitro and in vivo, and are associated with the risk reduction of colorectal cancer. It remains unknown, however, whether statin is effective for the treatment of inflammatory bowel disease (IBD). Therefore, we investigated anti-inflammatory effects of simvastatin on intestinal epithelial cells (IEC) and on an experimental murine colitis model, and elucidated its molecular mechanisms. Simvastatin (50 μM) significantly inhibited TNF-α-induced IL-8 gene expression in COLO 205 cells. Simvastatin (50 μM) blocked TNF-α-induced NF-κB transcriptional activity, IκB phosphorylation/degradation and DNA binding activity of NF-κB. Administration of simvastatin significantly reduced the severity of dextran sulfate sodium (DSS)-induced murine colitis as assessed by body weight, colon length, DAI, and histology in a dose-dependent manner. These results suggest that simvastatin inhibits proinflammatory gene expression by blocking NF-κB signaling in IEC, and attenuates DSS-induced acute murine colitis. Simvastatin could be a potential agent for the treatment of IBD.

Introduction

Inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) is a chronic intestinal inflammatory disease characterized by tissue edema, increased gut epithelial permeability, and extensive infiltration of the gut by leukocytes [1], [2]. Although great advances have been made in the management of the disease with the introduction of immunomodulators and biologic agents, a curative therapy does not yet exist. Therefore, it is still challenging to develop novel specific therapies for IBD [3].

Recent studies have demonstrated increased production of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-8 in IBD that are known to play a key role in the modulation of intestinal immune system [4], [5], [6]. The nuclear transcription factor κB (NF-κB) is a key regulator of the inducible expression of numerous genes involved in immune and inflammatory responses in the gut [7], [8], [9]. Sustained activation of NF-κB is thought to be pivotal in the pathophysiology of chronic intestinal inflammation. Increased NF-κB activation has been detected in the intestinal lamina propria of patients with Crohn's disease [10], [11], and in a murine TNBS (trinitrobenzene sulphonic acid) colitis model [12]. Activation of this transcription factor then upregulates the expression of numerous proinflammatory genes involved in intestinal inflammation. Growing evidence in the association of NF-κB activation and IBD suggests that the modulation of NF-κB signaling pathway could be the main target for the anti-inflammatory treatment of IBD [8], [13].

Statins are a new class of anticholesteremic 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors and have several beneficial effects on the cardiovascular system not strictly related to their effects on cholesterol metabolism [14], [15], [16], [17], [18], [19], [20]. During the past several years these beneficial effects of statins have been identified which includes anti-inflammatory and immunomodulatory properties. Despite the increasing number of reports describing anti-inflammatory effects of statins, the molecular mechanisms of these effects remain to be elucidated. In every inflammatory process, the vast majority of cellular events require NF-κB transcriptional activity. Several studies have revealed that anti-inflammatory effects of statins are related to the modulation of NF-κB signaling pathway in vascular endothelial and smooth muscle cells, and monocytes [21], [22], [23], [24], [25], [26]. In addition, two studies reported that pravastatin [27] and rosuvastatin [28] reduced disease activity and colonic inflammation in dextran sulfate sodium (DSS)-induced colitis in mice. However, the anti-inflammatory mechanisms of statins on intestinal epithelial cells (IEC) and the experimental colitis still remain unknown.

Therefore, we aimed to investigate anti-inflammatory effects of simvastatin on IEC and on an experimental murine colitis model, and to elucidate its molecular mechanisms.