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Synergistic effect of interleukin-10-receptor variants in a case of early-onset ulcerative colitis.
- Source :
-
World journal of gastroenterology [World J Gastroenterol] 2013 Dec 14; Vol. 19 (46), pp. 8659-70. - Publication Year :
- 2013
-
Abstract
- Aim: To investigated the molecular cause of very early-onset ulcerative colitis (UC) in an 18-mo-old affected child.<br />Methods: We analysed the interleukin-10 (IL10) receptor genes at the DNA and RNA level in the proband and his relatives. Beta catenin and tumor necrosis factor-α (TNFα) receptors were analysed in the proteins extracted from peripheral blood cells of the proband, his relatives and familial adenomatous polyposis (FAP) and PTEN hamartoma tumor syndrome (PHTS) patients. Samples were also collected from the proband's inflamed colorectal mucosa and compared to healthy and tumour mucosa collected from a FAP patient and patients affected by sporadic colorectal cancer (CRC). Finally, we examined mesalazine and azathioprine effects on primary fibroblasts stabilised from UC and FAP patients.<br />Results: Our patient was a compound heterozygote for the IL10RB E47K polymorphism, inherited from his father, and for a novel point mutation within the IL10RA promoter (the -413G->T), inherited from his mother. Beta catenin and tumour necrosis factor α receptors-I (TNFRI) protein were both over-expressed in peripheral blood cells of the proband's relatives more than the proband. However, TNFRII was over-expressed only in the proband. Finally, both TNFα-receptors were shown to be under-expressed in the inflamed colon mucosa and colorectal cancer tissue compared to healthy colon mucosa. Consistent with this observation, mesalazine and azathioprine induced, in primary fibroblasts, IL10RB and TNFRII over-expression and TNFRI and TNFα under-expression. We suggest that β-catenin and TNFRI protein expression in peripheral blood cells could represent molecular markers of sub-clinical disease in apparently healthy relatives of patients with early-onset UC.<br />Conclusion: A synergistic effect of several variant alleles of the IL10 receptor genes, inherited in a Mendelian manner, is involved in UC onset in this young child.
- Subjects :
- Adenomatous Polyposis Coli genetics
Adenomatous Polyposis Coli immunology
Age of Onset
Anti-Infective Agents pharmacology
Azathioprine pharmacology
Biomarkers blood
Cells, Cultured
Colitis, Ulcerative drug therapy
Colitis, Ulcerative immunology
Colitis, Ulcerative metabolism
Colon drug effects
Colon immunology
Colon metabolism
Colorectal Neoplasms genetics
Colorectal Neoplasms immunology
Female
Fibroblasts drug effects
Fibroblasts immunology
Fibroblasts metabolism
Gastrointestinal Agents pharmacology
Genetic Predisposition to Disease
Hamartoma Syndrome, Multiple genetics
Hamartoma Syndrome, Multiple immunology
Heredity
Humans
Infant
Interleukin-10 Receptor alpha Subunit metabolism
Interleukin-10 Receptor beta Subunit metabolism
Intestinal Mucosa drug effects
Intestinal Mucosa immunology
Intestinal Mucosa metabolism
Male
Mesalamine pharmacology
Pedigree
Phenotype
Promoter Regions, Genetic
RNA, Messenger metabolism
Receptors, Tumor Necrosis Factor, Type I blood
Receptors, Tumor Necrosis Factor, Type II blood
beta Catenin blood
Colitis, Ulcerative genetics
Interleukin-10 Receptor alpha Subunit genetics
Interleukin-10 Receptor beta Subunit genetics
Point Mutation
Polymorphism, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 2219-2840
- Volume :
- 19
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- World journal of gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 24379584
- Full Text :
- https://doi.org/10.3748/wjg.v19.i46.8659