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An Essential Role for the NLRP3 Inflammasome in Post-Infectious Irritable Bowel Syndreome

Author: FengJingJing
Tutor: LiYanQing
School: Shandong University
Course: Internal Medicine
Keywords: NALP3 Inflammasome Interleukin-1β Caspase-1 Ulcerative Colitis Post-Infectious Irritable Bowel Syndrome
CLC: R574.4
Type: Master's thesis
Year: 2011
Downloads: 107
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Abstract


Background & Aims:There is increasing evidence for involvement of the low grade inflammation in the pathogenesis of irritable bowel syndrome (IBS) particularly post-infectious IBS (PI-IBS). The Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome, an intracellular complex that regulates the release of proinflammatory cytokines interleukin-1β(IL-1β), have been revealed to play an important role in the pathogenesis of Crohn’s disease (CD) and experimental models of colitis, however, the role of NLRP3 in PI-IBS has not been characterized. This study was designed to examine the role of the NLRP3 inflammasome in PI-IBS.Methods:Colonic mucosal tissues were obtained from 32 PI-IBS patients (16 constipation-,16 diarrhea-predominant),16 UC patients and 16 healthy controls. The expression of NLRP3 in colonic tissue was identified by western blot, and the colonic content of IL-1βand caspase-1 were determined by enzyme-linked immunosorbent assay (ELISA). Stimulating HT-29 cells with tumor necrosis factor-α(TNF-α), muramyl dipeptide(MDP)and flagellin respectively. The expression of NLRP3 in cells was identified by western blot, and IL-1βin the supernatant was determined by ELISA.Results:UC patients, PI-IBS-C patients and PI-IBS-D patients exhibited significantly greater expression of IL-1βin colon mucosa than normal controls (p<0.001; p=0.001; p=0.020; respectively). UC patients and PI-IBS-C patients have statistically greater concentration of caspase-lin colon mucosa than controls (p=0.003; p=0.016; respectively), In addition, PI-IBS-D patients also expressed greater levels of caspase-1, but this didn’t reach statistical significance (p=0.081). Immunohistochemistry revealed the presence of NLRP3 mainly in inflammatory cells within mucosa, quantification of NLRP3 expression by counting the gray level and NLRP3 positive cells in the colon mucosa revealed that UC patients (p<0.001; p<0.001; respectively), PI-IBS-C patients (p<0.001; p<0.001; respectively) and PI-IBS-D patients (p=0.002; p<0.001; respectively) all exhibited significantly greater expression of NLRP3 than that of normal controls. Western blot analysis showed increased expression of NLRP3 in UC patients and PI-IBS-D patients than normal controls (p<0.001; p=0.032; respectively). In addition, PI-IBS-C patients expressed critical statistical significant level of NLRP3 than that of controls (p=0.051). No significant differences were observed between PI-IBS-C and PI-IBS-D patients for the above-mentioned factors. The increase in IL-1βcorrelated significantly with the increase in caspase-land NLRP3(r= 0.793, P<0.001; r=0.605, P<0.001; respectively) confirming that IL-1βsecretion is caspase-1 and NLRP3 dependent. For the results of cell culture, no expression of NLRP3 was detected, and no significant differences were observed among groups with different stimulators (p>0.05) and between groups with different stimulating time course (p>0.05).Conclusions:These findings indicate that those patients who develop PI-IBS and UC exhibited greater IL-1β, NLRP3 and caspase-1 expression, compared with healthy controls. Our data confirmed that caspase-1 dependent IL-1βsecretion via the NLRP3 inflammasome played an important role in the pathogenesis of PI-IBS and UC. In addition, the NLRP3 expressed in inflammatory cells, rather than that in colonic epithelial cells, played an important role in this process. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with PI-IBS and UC.

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CLC: > Medicine, health > Internal Medicine > Digestive and abdominal diseases > Bowel disease > Gastro-intestinal disorders
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