Nitric oxide pathway-related gene alterations in inflammatory bowel disease.
OBJECTIVE
To reveal specific gene activation in nitric oxide (NO)-related inflammation we studied differential gene expression in inflammatory bowel disease (IBD).


METHODS
Total RNA was isolated from 20 biopsies of inflamed mucosa from Crohn's disease (CD) and ulcerative colitis (UC) patients each as well as from six controls, labeled with (32)P-dCTP and hybridized to a human NO gene array. Significant genes were analyzed for functional gene interactions and heatmaps generated by hierarchical clustering. A selection of differentially expressed genes was further evaluated with immunohistochemical staining.


RESULTS
Significant gene expression differences were found for 19 genes in CD and 23 genes in UC compared to controls, both diseases with high expression of ICAM1 and IL-8. Correlation between microarray expression and corresponding protein expression was significant (r = 0.47, p = 0.002). Clustering analysis together with functional gene interaction analysis revealed clusters of coregulation and coexpression in CD and UC: transcripts involved in angiogenesis, inflammatory response mediated by the transcription factor hypoxia-inducible factor 1, and tissue fibrosis. Also, a fourth cluster with transcripts regulated by the transcription factor Sp1 was found in UC.


CONCLUSIONS
Expression analysis in CD and UC revealed disease-specific regulation of NO-related genes, which might be involved in perpetuating inflammatory disease activity in IBD.
Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Linda
L
Gillberg
Mark
M
Varsanyi
Mattias
M
Sjöström
Mikael
M
Lördal
Johan
J
Lindholm
Per M
PM
Hellström
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D016000:Cluster Analysis; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000235:genetics; D018709:Statistics, Nonparametric; D055815:Young Adult
D051793:Hypoxia-Inducible Factor 1; C573420:ICAM1 protein, human; D053583:Interleukin-1beta; D016209:Interleukin-8; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1