Enteric Glial Protein S100-Beta Modulates Intestinal Mucosa Inflammation in Celiac Disease

The enteric nervous system (ENS) is involved in the homeostasis of the whole gastrointestinal tract. Enteric glia, as part of the ENS, controls the physiological release of neurotrophic factors and participates to the inflammatory responses in animals. In the central nervous system increased expression of astroglial derived S100β protein has been recently associated with the onset and maintaining of inflammation. The role of enteric glial-S100β protein in the gastrointestinal inflammation has never been investigated in humans. We aimed to evaluate the role of S100β protein in patients with celiac disease that is a well characterized gut chronic inflammation. Duodenal biopsies from 30 patients with celiac disease (15 untreated and 15 on gluten-free diet) and 10 controls were evaluated for S100β protein expression, the iNOS expression and nitrite production. To further test whether S100β was able to modulate the inflammation, biopsies deriving from controls were stimulated for 3- 6-24 hours with exogenous purified S100β (0.005-5 μM) and iNOS protein expression and nitrite were measured. Also, lipid peroxidation and p38-MAPkinase activation were evaluated by adding S100β alone or in the presence of specific inhibitor of p38-MAPkinase and NFkappa B transcription factor, SB203580 and TLCK, respectively. Results. In untreated celiac patients the S100β protein expression, the iNOS protein expression and nitrites were significantly increased respectively by 399±7.1%, 2537±20% and 247±7.3% as compared to celiacs on gluten-free diet and controls. In cultured duodenal biopsies derived from healthy subjects, incubation with S100β induced a 40 fold increase of iNOS expression and a concentrationdependent increase of the nitrite production [65.5±2.5, 213.8±4.8, 397.4±9.0, 749±12.6%]. The effect of S100β (5 μM) on lipid peroxidation was significantly inhibited by increasing concentration of both SB203580 (0.03; 0.3; 3 μM) [29.7±4.1, 49.3±3.5, 72.6±5.8%] and TLCK (0.01; 0.1; 1 μM) [49.3±4.8, 66.0±5.1, 80±4.4%]. We found for the first time that S100β is increased in the duodenum of patients with celiac disease. This protein seems to modulate duodenal inflammation through induction of iNOS protein expression and nitrite production via p38-MAPkinase activation. Finally, our data highlight the importance of glial cell activation in pathophysiology of celiac disease and more extensively of gastrointestinal inflammation