Allele-specific induction of IL1B -31T/C promoter polymorphism by lung carcinogens.
Environmental and occupational toxicants may induce pulmonary inflammation. Chronic inflammation has been linked to several human diseases and also to initiation and promotion of cancer. Generation of reactive oxygen/nitrogen species (ROS/RNS), secretion of cytokines, chemokines and pro-angiogenic factors are believed to play a role. Interleukin IL-1beta, encoded by the IL1B gene, is a key cytokine produced and secreted by many cell types after activation by biological or chemical agents. Several polymorphisms in the IL1B gene have been identified, and some are associated with increased risk for lung cancer. Especially, the IL1B -31T/C polymorphism has received attention. We have investigated the effect of the lung carcinogens cigarette-smoke condensate (CSC) and benzo[a]pyrene (B[a]P) on the promoters of the IL1B gene varying only at the site of the -31T/C polymorphism. The promoter fragments containing either C or T were cloned in luciferase reporter vectors and transfected into human lung epithelial NCI-H2009 cells. The results show that treatment of the transfected cells with CSC or B[a]P induced the promoter significantly above the control level. Interestingly, the promoter with the wild-type allele T in position -31 showed the stronger induction when compared with the promoter with variant allele C in this position. Bioinformatics and DNA-protein analysis indicated the presence of a novel transcription-factor binding site and the formation of protein complexes at the C promoter.
Hart
Kent
K
Section of Toxicology, Department of Chemical and Biological Work Environment, National Institute of Occupational Health, Pb 8149 Dep., N-0033 Oslo, Norway.
Haugen
Aage
A
Zienolddiny
Shanbeh
S
D000483:Alleles; D001564:Benzo(a)pyrene / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D005838:Genotype; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics*; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014026:Nicotiana; D014162:Transfection
D002273:Carcinogens; C508585:IL1B protein, human; D053583:Interleukin-1beta; D001564:Benzo(a)pyrene