Increased mucosal nitric oxide production in ulcerative colitis is mediated in part by the enteroglial-derived S100B protein (original) (raw)
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Gut, 2003
Background: Intestinal inflammation in Crohn's disease (CD) and ulcerative colitis (UC) is characterised by an influx of neutrophils into the intestinal mucosa. S100A12 is a calcium binding protein with proinflammatory properties. It is secreted by activated neutrophils and interacts with the multiligand receptor for advanced glycation end products (RAGE). Promising anti-inflammatory effects of blocking agents for RAGE have been reported in murine models of colitis. Aims: To investigate expression and serum concentrations of S100A12 in inflammatory bowel disease (IBD). Methods: We performed immunohistochemical studies and immunofluorescence microscopy in biopsies from patients with CD and UC. S100A12 serum concentrations were analysed using a sandwich ELISA. Results: Immunohistochemical studies revealed profound expression of S100A12 in inflamed intestinal tissue from IBD patients whereas no expression was found in tissue from healthy controls. Staining for S100A12 during chronic active CD and UC was restricted to infiltrating neutrophils. Serum S100A12 levels were significantly elevated in patients with active CD (470 (125) ng/ml; p<0.001, n=30) as well as those with active UC (400 (120) ng/ml; p<0.01, n=15) compared with healthy controls (75 (15) ng/ml; n=30). Even in inactive disease, elevated serum concentrations were found, at least in CD. S100A12 levels were well correlated with disease activity in CD and UC. Conclusions: We demonstrated that neutrophil derived S100A12 is strongly upregulated during chronic active IBD, suggesting an important role during the pathogenesis of IBD. Serum S100A12 may serve as a useful marker for disease activity in patients with IBD.
S100B protein in the gut: The evidence for enteroglial-sustained intestinal inflammation
World Journal of Gastroenterology, 2011
Glial cells in the gut represent the morphological and functional equivalent of astrocytes and microglia in the central nervous system (CNS). In recent years, the role of enteric glial cells (EGCs) has extended from that of simple nutritive support for enteric neurons to that of being pivotal participants in the regulation of inflammatory events in the gut. Similar to the CNS astrocytes, the EGCs physiologically express the S100B protein that exerts either trophic or toxic effects depending on its concentration in the extracellular milieu. In the CNS, S100B overexpression is responsible for the initiation of a gliotic reaction by the release of pro-inflammatory mediators, which may have a deleterious effect on neighboring cells. S100B-mediated pro-inflammatory effects are not limited to the brain: S100B overexpression is associated with the onset and maintenance of inflammation in the human gut too. In this review we describe the major features of EGCs and S100B protein occurring in intestinal inflammation deriving from such.
The Importance of the Enteric Glia and its Related Product S100b Protein in Gut Inflammation
The urgent need of new pharmacological approaches that may enlarge the tools against inflammatory bowel diseases, lowering side effects and costs of the actually-used drugs is a very important challenge for gastroenterologists and pharmacologists. This short communication is aimed to highlight the importance of enteric glia and its derived signaling molecule S100B in the pathogenesis of chronic inflammation occurring in the gut. Once hyper-secreted, S100B, a small signaling diffusible Ca 2+ /Zn 2+ -binding protein, orchestrates a massive pro-inflammatory reaction in the gut, through the paracrine induction of nitric oxide and the recruitment of immune cells in the mucosa. A better understanding of the mechanisms by which enteric glia may trigger and perpetuate gut inflammation may address scientists to selectively target this cell population and decrease S100B overproduction may thus represent a significant innovation in this sense and open the field to novel therapies for inflammatory bowel diseases.
Digestive and Liver Disease, 2009
The urgent need of new pharmacological approaches that may enlarge the tools against inflammatory bowel diseases, lowering side effects and costs of the actually-used drugs is a very important challenge for gastroenterologists and pharmacologists. This short communication is aimed to highlight the importance of enteric glia and its derived signaling molecule S100B in the pathogenesis of chronic inflammation occurring in the gut. Once hyper-secreted, S100B, a small signaling diffusible Ca 2+ /Zn 2+-binding protein, orchestrates a massive pro-inflammatory reaction in the gut, through the paracrine induction of nitric oxide and the recruitment of immune cells in the mucosa. A better understanding of the mechanisms by which enteric glia may trigger and perpetuate gut inflammation may address scientists to selectively target this cell population and decrease S100B overproduction may thus represent a significant innovation in this sense and open the field to novel therapies for inflammatory bowel diseases.
The Serum S100B Level as a Biomarker of Enteroglial Activation in Patients with Ulcerative Colitis
International Journal of Inflammation, 2014
Objective. Recent studies have demonstrated that enteric glial cells (EGC) participate in the homeostasis of the gastrointestinal tract. This study investigated whether enteroglial markers, including S100B protein and glial fibrillary acidic protein (GFAP), can serve as noninvasive indicators of EGC activation and disease activity in UC patients. Methods. This clinical prospective study included 35 patients with UC and 40 age-and sex-matched controls. The diagnosis of UC was based on standard clinical, radiological, endoscopic, and histological criteria. Clinical disease activity was evaluated using the Modified Truelove-Witts Severity Index. Serum samples were analyzed for human GFAP and S100B using commercial enzyme-linked immunosorbent assay kits. Results. GFAP was not detected in the serum of either UC patients or controls ( > 0.05). However, we found a significant ( < 0.001) decrease in the serum S100B levels in the UC patients. No correlation between the serum S100B level and the disease activity or duration was observed ( > 0.05). The serum S100B levels did not differ between UC patients with active disease (24 patients, 68.6%) or in remission (11 patients, 31.4%) ( > 0.05). Conclusions. Ulcerative colitis patients had significantly lower serum S100B levels, while GFAP was of no diagnostic value in UC patients.
Neurogastroenterology & Motility, 2011
Background Enteric glial cells (EGCs) have been recently indicated as key regulators of intestinal inflammation in animals. Whether or not this is true and how these cells participate to inflammatory responses in humans is unknown. Methods We isolated primary EGCs from human small bowel and then, we purified and characterized those using specific glial markers, such as S100B and glial fibrillary acidic protein (GFAP). To mimic an inflammatory scenario, we exposed EGCs to exogenous stimuli, such as lipopolysaccharide and interferon-gamma (LPS and IFN-c), alone or in combination, to evaluate glial activation [measuring GFAP, S100B level together with c-fos, major histocompatibility complex (MHC) class II, inducible nitric oxide (iNOS) proteins expression and nitric oxide (NO) production] and proliferation, respectively. Key Results We showed that, when challenged with a combination of LPS and IFN-c, EGCs are significantly activated, as indicated by their positivity to c-fos and MHC class II. Similarly, pro-inflammatory stimuli significantly increase the cell proliferation rate, the expression of both S100B and GFAP, and the NO production consequent to the induction of EGCs-derived iNOS protein, with the last being dependent on S100B-RAGE (receptor for advanced glycation endproducts) interaction. Conclusions & Inferences Our data provide the first evidence that human EGCs directly respond to pro-inflammatory stimuli by changing their expression profile and by proliferating. The finding that stimulated EGCs are able to produce NO points to a role of this cell population in the scenario of intestinal inflammation.
Life Sciences, 2006
S100h is an astroglial-derived Ca 2+ -binding protein having neurotrophic role on neurons and glial cells. An aberrant S100h production has been observed in neurodegenerative disease, as Alzheimer's disease and Down syndrome. S100h is responsible to start up a gliotic reaction by the release of pro-inflammatory mediators, including nitric oxide (NO) and cytokines from microglia and astrocytes, which are, in turn, deleterious for neurons. Interestingly, pro-inflammatory effect of S100h seems not be restricted into the brain. Macrophages play a pivotal role in inflammatory diseases, occurring both in the brain and in the periphery. In this study, we tested the hypothesis that S100h may affect macrophage functions, amplifying thus the inflammatory process. Our results demonstrate that S100h stimulates both NO production and iNOS protein transcription and expression in J774 and rat peritoneal macrophages. NO production was concentration and time-dependently inhibited by two iNOS inhibitors, l-NAME and SMT. We also demonstrated that S100h induced oxidative stress by increasing H 2 O 2 production and lipid peroxidation of cell membrane in both macrophage types. The pro-oxidant potential of S100h activates p38 MAP kinase (MAPK), which has been described to directly activate NF-nB. In our study, SB203580, a p38 MAPK inhibitor, and two NF-nB inhibitors, TLCK and BAY 11-7082, decreased both NO production and iNOS protein transcription and expression in S100h-stimulated J774 and peritoneal rat macrophages. Moreover, additional studies demonstrated that S100h affected also TNF-a protein expression in J774 macrophages. In conclusion, our results highlight the potential role of S100h during an inflammatory scenario identifying macrophages as a novel S100h-responsive cell-type. D
The Journal of Pathology, 1998
Nitric oxide (NO) and reactive oxygen species (ROS) are important mediators in the pathogenesis of inflammatory bowel disease (IBD). NO in IBD can either be harmful or protective. NO can react with superoxide anions (O 2 • • • • •-) yielding the toxic oxidizing agent peroxynitrite (ONOO -). Peroxynitrite induces nitration of tyrosine residues (nitrotyrosine) leading to changes of protein structure and function. The aim of this study was to identify the cellular source of inducible nitric oxide synthase (iNOS), and to localise superoxide anion producing cells in mucosal biopsies from patients with active IBD. Additional studies were performed to look at nitrotyrosine formation as a measure of peroxynitrite mediated tissue damage. For this antibodies against iNOS, eNOS, and nitrotyrosine were used. ROS producing cells were detected cytochemically. Inflamed mucosa of patients with active IBD showed intense iNOS staining in the epithelial cells. iNOS could not be detected in non-inflamed mucosa of IBD patients and control subjects. eNOS was present in blood vessels, without any difference in staining intensity between IBD patients and control subjects. ROS producing cells were increased in the lamina propria of IBD patients, a fraction of these cells were CD 15 positive. Nitrotyrosine formation was found on ROS positive cells. These results show that iNOS is induced in epithelial cells from patients with active ulcerative colitis or Crohn's disease. Nitration of proteins was only detected in the ROS producing cells at some distance from the iNOS producing epithelial cells. These findings indicate that tissue damage during active inflammation in IBD patients is probably more related to ROS producing cells than to NO. One may speculate that NO has a protective role when during active inflammation other mucosal defence systems are impaired.