title: Interleukin-1β increases the risk of gastric cancer through induction of aberrant DNA methylation in a mouse model.
abstract: Interleukin-1β (IL-1β) has a significant role in chronic gastric inflammation and manifestations of gastric diseases. The present study aimed to elucidate the specific role of IL-1β in induction of DNA methylation using IL-1 receptor type 1 knockout (IL-1R1-/-) mice. In the present study, wild-type (WT) and IL-1R1-/-mice were injected with IL-1β (5 µg/kg/day). Serum levels of IL-1β, interleukin-6 (IL-6) and nitric oxide (NO) were measured by enzyme-linked immunosorbent or NO assays. E-cadherin (E-cad) methylation status and messenger (m)RNA expression of IL-1β, IL-6, E-cad and inducible nitric oxide synthase (iNOS) were analyzed. Results from the present study indicated significantly higher IL-1β mRNA expression (P<0.001) in WT mice compared with IL-1R1-/-mice. IL-1β and IL-6 release was significantly increased in treated WT mice compared with IL-1R1-/-mice at 1 h, 4 h and 8 h (all P<0.005). IL-1β release was only detected in WT mice following a second dose measured at day 3, week 1 and week 2 when compared with IL-1R1-/-mice. Promoter methylation of E-cad and a decrease in gene expression was observed in treated WT mice. mRNA expression of iNOS in WT mice was significantly increased at week 1 compared with IL-1R1-/-mice (P=0.0411). Furthermore, a significantly increased level of NO production was observed in treated WT mice (P<0.005 at 8 h and week 1; P<0.001 at 4 h and day 3) when compared with IL-1R1-/-mice. The present results indicated that IL-1β was able to directly induce DNA methylation, which may link inflammation-induced epigenetic changes and the development of gastric diseases.
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China.
authors.forename: Fung-Yu
authors.initials: FY
authors.lastname: Huang
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China; Gastroenterology and Hepatology Center, The Hong Kong Sanatorium and Hospital, Hong Kong, SAR, P.R. China.
authors.forename: Annie On-On
authors.initials: AO
authors.lastname: Chan
authors.affiliation: Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China.
authors.forename: Danny Ka-Ho
authors.initials: DK
authors.lastname: Wong
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China.
authors.forename: Wai-Kay
authors.initials: WK
authors.lastname: Seto
authors.affiliation: School of Biomedical Sciences and Institute of Digestive Diseases, Faculty of Medicine, The Chinese University of Hong Kong, SAR, P.R. China.
authors.forename: Chi-Hin
authors.initials: CH
authors.lastname: Cho
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China.
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Lai
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China.
authors.forename: Man-Fung
authors.initials: MF
authors.lastname: Yuen
keywords: DNA methylation; gastric cancer; inflammation; interleukin-1 receptor type 1 knockout mice; interleukin-1β