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. 2012 Dec;18(12):2342-56.
doi: 10.1002/ibd.22957. Epub 2012 Mar 29.

Immune markers and differential signaling networks in ulcerative colitis and Crohn's disease

George P Christophi  1 , Rong Rong, Philip G Holtzapple, Paul T Massa, Steve K Landas
Affiliations

Immune markers and differential signaling networks in ulcerative colitis and Crohn's disease

George P Christophi et al. Inflamm Bowel Dis. 2012 Dec.

Abstract

Background: Cytokine signaling pathways play a central role in the pathogenesis of inflammatory bowel disease (IBD). Ulcerative colitis (UC) and Crohn's disease (CD) have unique as well as overlapping phenotypes, susceptibility genes, and gene expression profiles. This study aimed to delineate patterns within cytokine signaling pathways in colonic mucosa of UC and CD patients, explore molecular diagnostic markers, and identify novel immune mediators in IBD pathogenesis.

Methods: We quantified 70 selected immune genes that are important in IBD signaling from formalin-fixed, paraffin-embedded (FFPE) colon biopsy samples from normal control subjects and UC and CD patients having either severe colitis or quiescent disease (n = 98 subjects). We utilized and validated a new modified real-time reverse-transcription polymerase chain reaction (RT-PCR) technique for gene quantification.

Results: Expression levels of signaling molecules including IL-6/10/12/13/17/23/33, STAT1/3/6, T-bet, GATA3, Foxp3, SOCS1/3, and downstream inflammatory mediators such as chemokines CCL-2/11/17/20, oxidative stress inducers, proteases, and mucosal genes were differentially regulated between UC and CD and between active and quiescent disease. We also document the possible role of novel genes in IBD, including SHP-1, IRF-1,TARC, Eotaxin, NOX2, arginase I, and ADAM 8.

Conclusions: This comprehensive approach to quantifying gene expression provides insights into the pathogenesis of IBD by elucidating distinct immune signaling networks in CD and UC. Furthermore, this is the first study demonstrating that gene expression profiling in FFPE colon biopsies might be a practical and effective tool in the diagnosis and prognosis of IBD and may help identify molecular markers that can predict and monitor response to individualized therapeutic treatments.

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Figures

Figure 1
Figure 1. Histology with Hematoxylin and Eosin staining representative of the colon biopsy tissue samples used in the study
Colon biopsy samples from IBD patients based on clinical history, endoscopic findings, and histopathological classification were used in the study. Disease severity was only determined by histopathologic criteria determined by two independent pathologists. A. Normal appearing colon from normal subjects (NS) B. Quiescent ulcerative colitis (qUC) – histologically normal-appearing colonic mucosa from a patient having documented UC based on both clinical and pathologic criteria, C. Severe inflammation in active UC (aUC), D. Quiescent Chron’s Disease (qCD) - histologically normal-appearing colonic mucosa from a patient having documented CD based on both clinical and pathologic criteria. The magnification in the pictures is 40 with the scale on the images showing 100 microns.
Figure 2
Figure 2. Cytokine gene expression in IBD
FFPE Colon biopsy samples from normal subjects (NS), active ulcerative colitis (aUC), quiescent UC (qUC), active Crohn’s Disease (aCD), and quiescent CD (qCD) were used to quantify gene expression using real time RT-PCR. Gene expression was normalized to NS, which was set to be 1. In histograms, * demonstrates a p value of 0.05-0.005 between the group and normal subjects, ** if p<0.005 between group and normal subjects, and δ if the p<0.05 between aUC and aCD.
Figure 3
Figure 3. Gene expression of mediators and modulators of cytokine signaling including transcription factors and phosphatase in IBD
FFPE Colon biopsy samples from normal subjects (NS), active ulcerative colitis (aUC), quiescent UC (qUC), active Crohn’s Disease (aCD), and quiescent CD (qCD) were used to quantify gene expression using real time RT-PCR. Gene expression was normalized to NS, which was set to be 1. In histograms, * demonstrates a p value of 0.05-0.005 between the group and normal subjects, ** if p<0.005 between group and normal subjects, and δ if the p<0.05 between aUC and aCD.
Figure 4
Figure 4. Gene expression of chemokines, chemokine receptors, and adhesion molecules in IBD
FFPE Colon biopsy samples from normal subjects (NS), active ulcerative colitis (aUC), quiescent UC (qUC), active Crohn’s Disease (aCD), and quiescent CD (qCD) were used to quantify gene expression using real time RT-PCR. Gene expression was normalized to NS, which was set to be 1. In histograms, * demonstrates a p value of 0.05-0.005 between the group and normal subjects, ** if p<0.005 between group and normal subjects, and δ if the p<0.05 between aUC and aCD.
Figure 5
Figure 5. Gene expression of cytokine-induced inflammatory genes that can mediate tissue injury in IBD
FFPE Colon biopsy samples from normal subjects (NS), active ulcerative colitis (aUC), quiescent UC (qUC), active Crohn’s Disease (aCD), and quiescent CD (qCD) were used to quantify gene expression using real time RT-PCR. Gene expression was normalized to NS, which was set to be 1. In histograms, * demonstrates a p value of 0.05-0.005 between the group and normal subjects, ** if p<0.005 between group and normal subjects, and δ if the p<0.05 between aUC and aCD.
Figure 6
Figure 6. Schematic summarizing the cytokine signaling pathways involved in IBD pathogenesis that were quantified in this study
* Designates that there is documented genetic association of the genes with IBD.
Figure 7
Figure 7. Vent diagram demonstrating gene expression in active or quiescent ulcerative colitis and Crohn’s disease
Potential genes that could be used in prospective studies to differentiate between UC and CD and correlate to disease severity.
See this image and copyright information in PMC

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