Mucosal Gene Expression of Cell Adhesion Molecules, Chemokines, and Chemokine Receptors in Patients With Inflammatory Bowel Disease Before and After Infliximab Treatment

Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
The American Journal of Gastroenterology (Impact Factor: 10.76). 02/2011; 106(4):748-61. DOI: 10.1038/ajg.2011.27
Source: PubMed


Inflammatory bowel disease (IBD) is characterized by a continuous influx of leukocytes into the gut wall. This migration is regulated by cell adhesion molecules (CAMs), and selective antimigration therapies have been developed. This study investigated the effect of infliximab therapy on the mucosal gene expression of CAMs in IBD.
Mucosal gene expression of 69 leukocyte/endothelial CAMs and E-cadherin was investigated in 61 IBD patients before and after first infliximab infusion and in 12 normal controls, using Affymetrix gene expression microarrays. Quantitative reverse transcriptase-PCR (qRT-PCR), immunohistochemistry, and western blotting were used to confirm the microarray data.
When compared with control colons, the colonic mucosal gene expression of most leukocyte/endothelial adhesion molecules was upregulated and E-cadherin gene expression was downregulated in active colonic IBD (IBDc) before therapy, with no significant colonic gene expression differences between ulcerative colitis and colonic Crohn's disease. Infliximab therapy restored the upregulations of leukocyte CAMs in IBDc responders to infliximab that paralleled the disappearance of the inflammatory cells from the colonic lamina propria. Also, the colonic gene expression of endothelial CAMs and of most chemokines/chemokine receptors returned to normal after therapy in IBDc responders, and only CCL20 and CXCL1-2 expression remained increased after therapy in IBDc responders vs. control colons. When compared with control ileums, the ileal gene expression of MADCAM1, THY1, PECAM1, CCL28, CXCL1, -2, -5, -6, and -11, and IL8 was increased and CD58 expression was decreased in active ileal Crohn's disease (CDi) before therapy, and none of the genes remained dysregulated after therapy in CDi responders vs. control ileums. This microarray study identified a number of interesting targets for antiadhesion therapy including PECAM1, IL8, and CCL20, besides the currently studied α4β7 integrin-MADCAM1 axis.
Our data demonstrate that many leukocyte/endothelial CAMs and chemokines/chemokine receptors are upregulated in inflamed IBD mucosa. Controlling the inflammation with infliximab restores most of these dysregulations in IBD. These results show that at least part of the mechanism of anti-tumor necrosis factor-α therapy goes through downregulation of certain adhesion molecules.

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    • "Particularly, this cytokine plays a critical role in the pathophysiology of IBDs, being involved in intestinal epithelial shedding and barrier dysfunction [45] [46]. These conditions are characterized by a dysregulated immune response, and monoclonal antibodies against TNFa have been proved as effective tools for treatment [20] [21]. Also, TNFa expression was found increased in a zebrafish larvae model of IBD, and these fish showed a positive response to immunomodulatory treatment [24]. "
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    • "The importance of anti-and proinflammatory balance is reflected in the efficacy of anti-TNF-í µí»¼ therapy in the treatment of IBD [5]: TNF-í µí»¼ inhibitors have proven successful in inducing and maintaining remission of moderateto-severe IBD. In addition, CXCL1 is a chemoattractant for neutrophils and plays a role in inflammation; increased ileal and colonic CXCL1 gene expression was also reported in IBD patients [6]. IBD is associated with enhanced production of reactive metabolites of oxygen and nitrogen (RONS). "
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    • "However, in a number of cases overreactions of the immune system due to inflammatory stimuli can be observed. In this context, proinflammatory immune modulators like interleukin 1 beta (IL-1í µí»½), monocyte chemoattractant protein 1 (MCP-1), and vascular cell adhesion molecule 1 (VCAM-1) play an important role in the development of the disease [1] [2]. Nuclear factor " kappalight-chain-enhancer " of activated B cells (NFí µí¼…B) represents a key transcription factor regulating the synthesis of genes involved in immune reactions and inflammatory response. "
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