Cytokines in Inflammatory Bowel Disease

Abstract

Cytokines play a central role in the modulation of the intestinal immune system. They are produced by lymphocytes (especially T cells of the Th1 and Th2 phenotypes), monocytes, intestinal macrophages, granulocytes, epithelial cells, endothelial cells, and fibroblasts. They have proinflammatory functions [interleukin-1 (IL-1), tumor necrosis factor (TNF), IL-6, IL-8, IL-12] or antiinflammatory functions [interleukin-1 receptor antagonist (IL-1ra), IL-4, IL-10, IL-11, transforming growth factor beta (TGF beta)]. Mucosal and systemic concentrations of many pro- and antiinflammatory cytokines are elevated in inflammatory bowel disease (IBD). An imbalance between proinflammatory and antiinflammatory cytokines was found for the IL-1/IL-1ra ratio in the inflamed mucosa of patients with Crohn's disease, ulcerative colitis, diverticulitis, and infectious colitis. Furthermore, the inhibition of proinflammatory cytokines and the supplementations with antiinflammatory cytokines reduced inflammation in animal models, such as the dextran sulfate colitis (DSS) model, the trinitrobenzene sulfonic acid (TNBS) model, or the genetically engineered model of IL-10 knockout mice. Based on these findings a rationale for cytokine treatment was defined. The first clinical trials using neutralizing monoclonal antibodies against TNF alpha (cA2) or the antiinflammatory cytokine IL-10 have shown promising results. However, many questions must be answered before cytokines can be considered standard therapy for IBD.

Proinflammatory cytokines and IL-10 in inflammatory bowel disease and colorectal cancer patients

“…The results point to a continuous activation of monocytes/macrophages in the course of IBD and correspond to other results (Hyun and Mayer 2006;Rogler and Andus 1998). Nevertheless, the causal factors beyond the activation of the cells are incompletely understood, although experiments on animal models provide evidence for the importance of antigens of commensal bacteria in stimulation of the mucosal immune system (Rennick and Fort 2000;Sartor 2004).…”

14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells

“…But, contrary to those reports where autophagy acts as a suicidal mechanism, 55,56 our results suggested that the major purpose of the accompanying increase in autophagy observed during inflammation is to fully activate Akt1, a major antiapoptotic signaling molecule. 16 However, the continuous cytokine stimulation of the inflamed mucosa 57,58 might result in the dysregulation of the machinery that controls Akt signaling pathway, leading to uncontrolled Akt activation and cell death. This is a plausible scenario because proinflammatory cytokines can also affect other biological processes that control Akt function such as protein synthesis 2 and/or Akt targeting/shuttling, 2 which is known to be important for controlling Akt destiny and function.…”

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

“…On microscopy, material from patients with pancolitis and patients with left-sided colitis differed principally in the degree of inflammation present (data not shown). Patients with IBD have a disturbed balance between pro-and anti-inflammatory cytokines in the mucosa, one possible reason why anticytokine treatment is efficient (Rogler and Andus, 1998), and the production of proinflammatory cytokines is higher in severe UC colitis than in colitis with lesser endoscopic grades of inflammation (Ishiguro, 1999;Raddatz et al, 2005). In our study, mRNA expression levels of iNOS, which in pancolitis is expressed after induction by certain cytokines, microbes, and bacterial products (Kolios et al, 2004), were significantly increased (15-fold), higher than in left-sided colitis (Table 5).…”