Original ArticleDifferential expression of the TRAIL/TRAIL-receptor system in patients with inflammatory bowel disease
Introduction
Tumor necrosis factor-related apoptosis inducing-ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family of cytokines. It is a potent inducer of apoptosis in several tumor cells but not in the majority of normal cells [13], [14], [19], [20], [21], [27], [36], [38]. Apoptosis is the physiological form of cell death, which is necessary for the removal of potentially dangerous cells, such as infected or transformed cells, and for the regulation of immune response [30]. It also plays an important role in tissue homeostasis, for instance, in the turnover of epithelial cells of the gastrointestinal mucosa [6]. Dysregulated apoptosis contributes to carcinogenesis and is involved in inflammatory damage in chronic inflammatory diseases, such as chronic arthritis and inflammatory bowel disease.
Upon TRAIL binding, TRAIL-R1 [26] and TRAIL-R2 [31], [35] mediate apoptosis via their cytoplasmic death domain. Two other receptors, TRAIL-R3 and TRAIL-R4, do not induce apoptosis because they both lack a functional death domain [9], [24], [25], thereby rather inhibiting TRAIL-induced apoptosis by competing with TRAIL-R1 and TRAIL-R2 for TRAIL binding. Furthermore, TRAIL-R4 has been shown to inhibit apoptosis through a ligand-independent association with TRAIL-R2 via the preligand assembly domain (PLAD) [7] or by NF-κB-activation [29]. The fifth TRAIL-receptor, osteoprotegerin, is a soluble receptor and is involved in the regulation of bone metabolism [11], [32].
Although the physiological role of TRAIL has not been completely understood so far, recent data demonstrate an important role of TRAIL as an inhibitory immune modulator. TRAIL −/− mice were more prone to collagen-induced arthritis, streptozotocin-induced diabetes [22], [23], experimental thyroiditis [37], and experimental autoimmune encephalitis [8]. Furthermore, upon infection with murine CMV or Listeria monocytogenes TRAIL-R −/− mice demonstrated an enhanced activation of the innate immune response in the late phase with elevated cytokine levels [10], [39]. This suggests that the TRAIL system might be involved in keeping the immune system in check. Thus, lack of the TRAIL system could unleash both immune and autoimmune responses.
Moreover, TRAIL is upregulated on activated immune cells and locally mediates cytotoxic effects on target cells at the site of inflammation. Thus, although TRAIL −/− mice were more prone to experimental autoimmune encephalitis, intrathecal injection of TRAIL-neutralizing antibodies in an encephalitis model of TRAIL-proficient mice could attenuate tissue damage [1]. Furthermore, TRAIL has been shown to mediate tissue damage in Hashimoto thyroiditis [33].
These new insights into the immunological functions of TRAIL and TRAIL receptors led to the question of whether they are also involved in the development of inflammatory bowel diseases (IBD), the most important of which are Crohn's disease (CD) and ulcerative colitis (UC). At present, there exist only few data on the precise molecular mechanisms that lead to epithelial destruction during inflammation in CD and UC. In the past few years, several mechanisms that might play a role in the pathogenesis of IBD were discussed. Recent data suggest that, for example, enhanced expression of chemokine receptors may be involved in the development of IBD [3]. Apoptosis is one of the key mechanisms that might influence immune functions as well as barrier functions of the gut. Evidence is increasing that a dysregulation of apoptosis in intestinal epithelial cells and immune cells is involved in the pathogenesis of IBD. In epithelial cells in IBD, increased apoptosis rates up to 5% in mild-to-moderately inflamed colon specimens have been reported, resulting in a disrupted barrier function [34]. Furthermore, many studies suggest that insufficient apoptosis in activated lymphocytes and monocytes might contribute to the development of IBD by an accumulation of inflammatory cells in IBD mucosa [2], [5], [16]. Thus, the disequilibrium between pro- and anti-apoptotic factors of epithelial and immune cells might play a causal role in the pathogenesis of inflammatory bowel disease. In line with this assumption, Begue et al. [4] showed TRAIL upregulation in epithelial cells in biopsy specimens from inflammatory colon and ileum. However, they did not observe any disease specificity. Therefore, in the present study, we analyzed the expression of the TRAIL/TRAIL-receptor system in intestinal epithelium and infiltrating immune cells in human colonic specimens of patients with IBD in comparison to normal colon tissue and appendicitis.
Section snippets
Patients and specimens
To analyze the expression of TRAIL, TRAIL-receptors and CD95 (APO-1) inflammatory colonic surgical specimens were taken after informed consent was obtained from patients with UC (n=10) and patients with CD (n=9), who underwent colon/ileal resection (Table 1). Nine patients with active UC were treated with proctocolectomy. One patient underwent subtotal colectomy. Nine patients with active CD had to be treated with bowel resection because of disease-specific complications, such as stenosis,
Results
We compared the expression of TRAIL, TRAIL receptors 1–4, and CD95 in disease-involved areas of the colonic mucosa of patients with UC, CD, normal colon, and appendicitis. All of these ligands and receptors revealed a predominant cytoplasmic staining.
Discussion
The pathogenesis of inflammatory bowel disease (IBD) is complex, involving environmental, genetic, microbial, and immune factors. The intestinal epithelium is in constant communication with luminal bacterial and nutritional antigens and the underlying dense network of innate and adaptive immune cells. Evidence is increasing that dysregulated apoptosis is involved in the pathogenesis of inflammatory bowel disease. TRAIL could exert both regulatory and effector functions in autoimmune diseases.
Acknowledgments
We thank Prof. Frank Autschbach (Institute of Pathology, University Hospital, Heidelberg) for his logistic support, and critical review of the manuscript and Jutta Mohr for her excellent technical assistance.
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