Differential and opposed transcriptional effects of interleukin-18 gene polymorphisms (-137, +113, and +127) in human HepG-2, HeLa, U937, and THP-1 cells
Xiao Hui Liang, Cheung Wai, De Yun Wang
Med Sci Monit 2008; 14(1): BR8-13
Available online: 2008-01-01
Polymorphisms in the IL-18 promoter region (-137, +113, and +127), with perfect linkage disequilibria (Delta=1, p<0.001) among them, were observed in Singaporean Chinese, Malays, and Indians. These polymorphisms appear to have no association with atopic phenotypes. However, functional studies indicate that IL-18 gene polymorphisms strongly affect its activity in cultured cells. The reasons for such conflicting results remain to be determined. It is likely that they are related to the responding cells or to the varying cytokine milieus in the course of the atopic diseases. In this study the effects of IL-18 gene polymorphisms in various IL-18-producing cells were investigated.
Material and Method: Three observed alleles were cloned and transfected into HepG-2, HeLa, U937, and THP-1 cells. The transfectional activities of the cultured cells were analyzed.
Results: Inserted fragments had significant, but opposite transfectional activity in HepG-2 and HeLa cells, while there was no difference in transfectional activity in U937 and THP-1 cells.
Conclusions: These data support the authors' previous observation in which they were unable to detect an association between IL-18 gene polymorphisms and atopic phenotypes in this population. This might be due to different regulatory elements that affect the functional assessment of polymorphisms in different IL-18-producing cells. The functional significance of genetic variants in experimental studies may not be consistent due to complex human traits, but it can also be due to variations in the experimental approaches used, such as the use of different cell or tissue types.
Keywords: Transcription, Genetic, Promoter Regions, Genetic, Polymorphism, Single Nucleotide, Polymorphism, Genetic, Interleukin-18 - genetics, Phenotype, Hypersensitivity, Immediate - immunology, Hela Cells, Haplotypes, Genotype, U937 Cells, Transfection, Cell Line, Asian Continental Ancestry Group - genetics, Adult, 5' Untranslated Regions