Mechanisms of action of infliximab in inflammatory bowel disease: an anti-inflammatory multitasker
ABSTRACT The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) plays a central role in mucosal inflammation and is a key mediator in the inflammatory cascade in both Crohn's disease (CD) and ulcerative colitis (UC). Infliximab, a monoclonal antibody against TNF-alpha has been proved highly effective in the clinical management of both forms of IBD. Aim of this paper is to review the mechanisms of action of infliximab in IBD.
- SourceAvailable from: Iyad A Issa
Inflammation, Chronic Diseases and Cancer - Cell and Molecular Biology, Immunology and Clinical Bases, 03/2012; , ISBN: 978-953-51-0102-4
- "The debate between uses of cyclosporine or IFX for patients with fulminant UC has been complicated by the complexity of monitoring cyclosporine IV compared to the ease of giving IFX [Janerot et al. 2006]. Additional questions remain regarding the need for long term dosing after anti-TNF induction therapy as ACT studies did not evaluate the long term responses and one may speculate that doses may need adjustment on the long term [Danese et al. 2008; Kohn et al. 2007]. "
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ABSTRACT: Background:The interleukin 10 knockout mouse (IL10-KO) is a model of human inflammatory bowel disease (IBD) used to study host microbial interactions and the action of potential therapeutics. Using Affymetrix data analysis, important signaling pathways and transcription factors relevant to gut inflammation and antiinflammatory probiotics were identified.Methods:Affymetrix microarray analysis on both wildtype (WT) and IL10-KO mice orally administered with and without the probiotic VSL#3 was performed and the results validated by real-time polymerase chain reaction (PCR), immunocytochemistry, proteomics, and histopathology. Changes in metabolically active bacteria were assessed with denaturing gradient gel electrophoresis (DGGE).Results:Inflammation in IL10-KO mice was characterized by differential regulation of inflammatory, nuclear receptor, lipid, and xenobiotic signaling pathways. Probiotic intervention resulted in downregulation of CXCL9 (fold change [FC] = −3.98, false discovery rate [FDR] = 0.019), CXCL10 (FC = −4.83, FDR = 0.0008), CCL5 (FC = −3.47, FDR = 0.017), T-cell activation (Itgal [FC = −4.72, FDR = 0.00009], Itgae [FC = −2.54 FDR = 0.0044]) and the autophagy gene IRGM (FC = −1.94, FDR = 0.01), a recently identified susceptibility gene in human IBD. Consistent with a marked reduction in integrins, probiotic treatment decreased the number of CCL5+ CD3+ double-positive T cells and upregulated galectin2, which triggers apoptosis of activated T cells. Importantly, genes associated with lipid and PPAR signaling (PPARα [FC = 2.36, FDR = 0.043], PPARGC1α [FC = 2.58, FDR = 0.016], Nr1d2 [FC = 3.11, FDR = 0.0067]) were also upregulated. Altered microbial diversity was noted in probiotic-treated mice.Conclusions:Bioinformatics analysis revealed important immune response, phagocytic and inflammatory pathways dominated by elevation of T-helper cell 1 type (TH1) transcription factors in IL10-KO mice. Probiotic intervention resulted in a site-specific reduction of these pathways but importantly upregulated PPAR, xenobiotic, and lipid signaling genes, potential antagonists of NF-κB inflammatory pathways. (Inflamm Bowel Dis 2009)Inflammatory Bowel Diseases 01/2009; 15(11):1721 - 1736. DOI:10.1002/ibd.20999 · 5.48 Impact Factor