Most of the AMP genes upregulated at baseline in active IBDc decreased significantly more than 2-fold after infliximab treatment in IBDc responders when compared to their baseline samples

Most of the AMP genes upregulated at baseline in active IBDc decreased significantly more than 2-fold after infliximab treatment in IBDc responders when compared to their baseline samples. infliximab. In ileal Crohn’s disease (CD), expression of two neuropeptides with antimicrobial activity,PYYandCHGB, was significantly decreased before therapy compared to control ileums, and ilealPYYexpression remained significantly decreased after therapy in CD responders. Expression of the downregulated AMPs before and after treatment (DEFB1andPYY) correlated with villin 1 expression, a gut epithelial cell marker, indicating that the decrease is a Rabbit Polyclonal to CRMP-2 consequence of epithelial damage. == Conclusions/Significance == Our study shows that the dysregulation of AMPs in IBD mucosa is the consequence of inflammation, but may be responsible for perpetuation of inflammation due to ineffective clearance of microorganisms. == Introduction == Inflammatory bowel diseases (IBDs), Crohn’s disease (CD) and ulcerative colitis (UC), are multifactorial diseases of unknown Moxonidine Hydrochloride etiology, characterized by chronic relapsing inflammation of the gastro-intestinal tract. Immune, genetic and environmental factors are thought to contribute to IBD[1]. Many findings suggest that the intestinal flora plays an important role in the pathogenesis of IBD. First, several knockout animal models of IBD in a germ-free environment fail to develop intestinal inflammation[2][6]. Second, recurrence of CD in the neoterminal ileum after ileal resection with ileocolonic anatomosis has been shown to be dependent on faecal stream[7]. Third, luminal contents trigger inflammation[8], and T-cell responses in CD patients are directed against the autologous bacterial flora[9]. Fourth, in CD mucosa adherentEscherichia colihas been found[10]. Finally, antibiotics and probiotics do often ameliorate the symptoms in IBD[11]. Together these points support the microbial contribution to IBD, indicating that a basic antimicrobial mucosal barrier defect could be responsible for susceptibility to this disease. The gastro-intestinal tract is constantly exposed to a wide range of microorganisms. In order to maintain the mucosal barrier integrity against these luminal microorganisms, the intestinal epithelial cells produce a variety of antimicrobial peptides (AMPs), like defensins, lysozyme and cathelicidins. AMPs contribute to innate immunity and can be considered as natural peptide antibiotics. Several recent studies Moxonidine Hydrochloride indicate that an abnormal expression of AMPs may exist in IBD[12]. Patients with Crohn’s ileitis (CDi) show a reduced antibacterial activity in their intestinal mucosal extracts and display a decreased expression of the Paneth cell alpha-defensins (DEFA5andDEFA6)[13]. In the study by Wehkamp et al.[14], this decrease was found independent of the degree of inflammation and associated withNOD2mutations. However, another study found no correlation between the decreased alpha-defensins expression and theNOD2status but linked the decrease to inflammation[15]. A study by Noble et al.[16]showed a regional variation ofDEFA5andDEFA6gene expression in non-inflamed intestinal biopsies of Moxonidine Hydrochloride normal subjects and UC patients, with high expression in the terminal ileum and expression decreasing as the biopsy location became more distal in the colon. They further found a marked upregulation ofDEFA5andDEFA6expression in inflamed UC colon. As compared to UC, Crohn’s colitis (CDc) is characterized by a decreased antimicrobial activity in cationic protein extracts from colonic biopsies and an attenuated induction of beta-defensins (DEFB4/HBD-2,DEFB103), cathelicidinLL37, and antimicrobial antiproteases elafin andSLPI[17][21]. The defective mRNA induction of beta-defensins in CDc may be partly due to lowDEFB4gene copy Moxonidine Hydrochloride number[22]. However, no association withDEFB4gene copy Moxonidine Hydrochloride number was found on DEFB4 protein level[23].TheDEFB1expression was found to be decreased in both active UC and CD[18]. It can be argued, however, that the abnormal AMP status of IBD patients is the consequence of an altered interaction between barrier and microflora interaction rather than a causative factor for disturbed microbial clearance. The hypothesis for the present study was that disturbed AMP expression in IBD is a pathogenic factor. When true, the prediction is that after pharmacological suppression of inflammation the underlying defective expression of AMPs would be unmasked. However, if the alternative hypothesis is true, namely that abnormalities in AMP production are a secondary phenomenon, it can be predicted that after disappearance of inflammation the AMP expression in IBD normalizes. To distinguish between these two hypotheses, we investigated the intestinal mucosal gene expression of AMPs in active IBD patients and the impact of anti-inflammatory therapy.

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