Strong overexpression of CXCR3 axis components in childhood inflammatory bowel disease.
BACKGROUND
Inflammatory bowel disease (IBD) is a polygenetic disorder. Our group previously showed that a variant within the CXCL9 gene is associated with pediatric Crohn's disease. As CXCL9, CXCL10, and CXCL11 are the 3 ligands to the receptor CXCR3, the aim of this study was to investigate the colonic transcriptional activity of the CXCR3 axis and to perform SNP genotyping of a CXCL11 polymorphism in a large pediatric and adult IBD cohort.


METHODS
mRNA expression of CXCR3, CXCL9, CXCL10, CXCL11, and IL8 was analyzed in colonic biopsies using real-time PCR. CXCL11 rs6817952 nucleotide substitution was determined in 501 German individuals with IBD (336 CD, 165 UC) including 258 children and 243 adults as well as in 231 controls by a TaqMan SNP genotyping assay.


RESULTS
CXCR3 axis genes were significantly overexpressed in inflamed colonic tissue of pediatric CD and UC patients. The prevalence of hetero- and homozygous variants of the rs6817952 genotype was higher in pediatric but not in adult CD patients compared with that in controls (P = 0.04). Moreover, carriers of the hetero- and homozygous genotype variants of rs6817952 were at increased risk for UC in all age groups (P = 0.009).


CONCLUSIONS
Our study provides evidence of the significant overexpression of the CXCR3 axis in active IBD, suggesting it has a role in IBD pathogenesis. The rs6817952 A variant is a risk allele for pediatric CD and UC in all age groups. Therapeutic studies will have to show whether the blockade of chemokine receptors such as CXCR3 can modulate intestinal inflammation in a clinical application.
Schroepf
Sebastian
S
Department of Pediatric Surgery, Research Laboratories, University of Munich, Munich, Germany.
Kappler
Roland
R
Brand
Stephan
S
Prell
Christine
C
Lohse
Peter
P
Glas
Jürgen
J
Hoster
Eva
E
Helmbrecht
Johanna
J
Ballauff
Antje
A
Berger
Michael
M
von Schweinitz
Dietrich
D
Koletzko
Sibylle
S
Lacher
Martin
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D054357:Chemokine CXCL10 / Q000032:analysis; D054371:Chemokine CXCL11 / Q000032:analysis; D054370:Chemokine CXCL9 / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003106:Colon / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D054367:Receptors, CXCR3 / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D055815:Young Adult
C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D016209:Interleukin-8; D054367:Receptors, CXCR3