Anti-TNF alpha polyclonal antibody [Biotin]

Objectives Cytokines play a pivotal role in inflammatory bowel disease (IBD). We investigated the expression of inflammatory and regulatory cytokines in inflamed and uninflamed mucosal samples of ulcerative colitis patients. Methods Twenty-five ulcerative colitis patients were enrolled. Bioptic samples from inflamed and not inflamed intestinal areas were obtained. Multiplex analysis for inflammatory and regulatory cytokines was performed. Serum C-reactive protein (CRP) was assessed. Endoscopic Mayo score and histological simplified Geboes score were calculated. Results Interleukin (IL)-1Ra, IL-6, IL-8, IL-17, induced Protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1a, MIP-1b resulted increased in ulcerative colitis inflamed vs ulcerative colitis not inflamed areas. No differences were registered between conventional and anti-tumor necrosis factor-a regimens. No difference with CRP levels was found. IL-7 resulted reduced in patients with endoscopic Mayo score >= 2. All the not inflamed samples had a Geboes score <2A, while all the inflamed specimens had a Geboes score >= 2B. IL-1Ra resulted increased in the group with a Geboes score >= 4. Conclusions Inflamed and adjacent not inflamed mucosal areas in ulcerative colitis patients share detailed inflammatory molecular pathways, but can be differentiated endoscopically and histologically on the basis of specific cytokines levels. This underlines the complexity of the mucosal cytokine network in ulcerative colitis and highlights the major limitations of a single proinflammatory target therapeutic strategy in IBD.

Objective Reduced Paneth cell (PC) numbers are observed in inflammatory bowel diseases and impaired PC function contributes to the ileal pathogenesis of Crohn's disease (CD). PCs reside in proximity to Lgr5(+) intestinal stem cells (ISC) and mitochondria are critical for ISC-renewal and differentiation. Here, we characterise ISC and PC appearance under inflammatory conditions and describe the role of mitochondrial function for ISC niche-maintenance. Design Ileal tissue samples from patients with CD, mouse models for mitochondrial dysfunction (Hsp60(Delta/Delta ISC)) and CD-like ileitis (TNF Delta ARE), and intestinal organoids were used to characterise PCs and ISCs in relation to mitochondrial function. Results In patients with CD and TNF Delta ARE mice, inflammation correlated with reduced numbers of Lysozyme-positive granules in PCs and decreased Lgr5 expression in crypt regions. Disease-associated changes in PC and ISC appearance persisted in non-inflamed tissue regions of patients with CD and predicted the risk of disease recurrence after surgical resection. ISC-specific deletion of Hsp60 and inhibition of mitochondrial respiration linked mitochondrial function to the aberrant PC phenotype. Consistent with reduced stemness in vivo, crypts from inflamed TNF Delta ARE mice fail to grow into organoids ex vivo. Dichloroacetate-mediated inhibition of glycolysis, forcing cells to shift to mitochondrial respiration, improved ISC niche function and rescued the ability of TNF Delta ARE mice-derived crypts to form organoids. Conclusion We provide evidence that inflammation-associated mitochondrial dysfunction in the intestinal epithelium triggers a metabolic imbalance, causing reduced stemness and acquisition of a dysfunctional PC phenotype. Blocking glycolysis might be a novel drug target to antagonise PC dysfunction in the pathogenesis of CD.