Abstract
The anti-inflammatory genes, haem oxygenase 1 (HO-1, HMOX1) rs2071746 (unrestricted model: p = 9.07 × 10-4; recessive model: p = 4.99 × 10-4; multiplicative model: p = 0.0009; and additive model: p = 1.87 × 10-4) and interleukin-10 (IL-10) rs1800872 (dominant model: p = 0.0277) have been associated with paediatric inflammatory bowel disease. The present family-based case-trio study (n = 52) examined HO-1 gene expression in the presence of proinflammatory lipopolysaccharide and tumour necrosis factor-alpha in four B lymphocyte cell lines established from children with inflammatory bowel disease and demonstrated that mutations in IL-10 and IL-10 receptor B reduced HO-1 messenger RNA expression. This observation supports our hypothesis that HO-1 is regulated by the IL-10/STAT3 pathway and that both genes (IL10 and STAT3) could be involved in the pathogenesis of inflammatory bowel disease. We also compared HO-1 expression in diseased intestinal tissues with adjacent normal tissues from adults with inflammatory bowel disease. Of the 17 Crohn's disease patients, HO-1 expression in diseased tissues was downregulated in 9 patients (53%) and of the 10 ulcerative colitis patients HO-1 was downregulated in 7 patients (70%), compared with adjacent normal tissues. The downregulation of HO-1 gene expression may lower anti-inflammatory effects and worsen tissue injury in affected areas by inflammatory bowel disease.
Highlights
Haem oxygenase 1 (HO-1) catalyses the degradation of haem to biliverdin and carbon monoxide
In biopsy specimens from 18 ulcerative colitis patients and 13 colon cancer patients, expression of HO-1 mRNA and protein was significantly increased in the colonic mucosa of patients with active ulcerative colitis compared with normal mucosa [25]. These results collectively indicate that there may be an induction of HO-1 in the colon of ulcerative colitis patients In the present study, we observed a downregulation of HO-1 expression in diseased intestinal tissues compared to adjacent normal tissues from 9 out of 17 Crohn’s disease patients (53%) and 7 out of 10 ulcerative colitis patients
We showed that single nucleotide polymorphisms (SNPs) rs1800872 of IL-10 and rs2071746 of HO-1 are associated with paediatric inflammatory bowel disease (IBD)
Summary
Haem oxygenase 1 (HO-1) catalyses the degradation of haem to biliverdin and carbon monoxide. In our case-control study (submitted for publication) we did not observe association of the HO-1 rs2071746 with paediatric IBD, which is consistent with the available literature. IL-10 and STAT3 SNPs have been shown to associate with IBD [7–10]. Mutations in IL-10 and IL-10 receptors (IL-10RA and IL-10RB) were shown to be associated with paediatric IBD [7, 11–14], and our recent case-control study (submitted) showed association of IL-10 SNP rs3024496 with paediatric IBD (p = 0.022), as well as an epistatic interaction (dominant-additive p = 0.0018) of IL-10RB (rs2834167) and HO-1 (rs2071746). In the present family based case-trio study, we hypothesised that HO-1 SNPs would be associated with paediatric IBD. We studied HO-1 gene expression in B lymphocyte cell lines from paediatric IBD patients carrying IBD-associated gene variants and their response to the inflammatory inducers, lipopolysaccharide (LPS) and tumour necrosis factor alpha (TNFα), as well as HO-1 gene expression in diseased and nondiseased tissues from adult IBD patients
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