Oct‐1 is responsible for the C‐33T polymorphism effect in the IL‐4 promoter

Abstract

IL-4 is a pleiotropic immunoregulatory cytokine secreted by Th2 subset of CD4(+) Th cells. Several transcription factors (TFs) have been determined with various degrees of certainty to bind the IL-4 promoter and to regulate its expression in human. To investigate the mechanisms responsible for phenotypic effects of the C-33T IL-4 promoter polymorphism, we performed a search of TFs binding to this promoter locus and discriminating the -33C and -33T alleles. In silico searches suggest few factors bind this region. Using an electromobility shift assay we found that Jurkat T cells contained proteins which specifically interacted with oligonucleotide probes, corresponding to the -33 region. Considerable binding differences between C and T alleles were demonstrated using competitive conditions, the proteins bound predominantly with -33C allele. We found that the transcription factor Oct-1 produced the major shifted complex. The binding of Oct-1 was not improved using activated nuclear extracts; however, we observed increases in other shifted complexes upon cell activation. We suppose that Oct-1 occupancy may compete for binding of activator proteins to closely or overlapped binding sites. Our findings suggest that the interplay between Oct-1 and unknown TFs may be responsible for the C-33T polymorphism effects.

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis

“…SNPs may influence protein conformation (topology), promoter activity, pre-mRNA and RNA splicing, or transcriptional regulation affecting cytokine production (65). Some SNPs in the IL-4 and TNF-␣ genes create a new binding site for the OCT-1 transcription factor affecting gene expression (66,67). In addition, the variability in IL-10 production associated with the presence of the IL-10 Ϫ819G/A polymorphism is related to the activation of poly(ADPribose) polymerase 1 (PPAR-1) and the suppression of IL-10 transcription (68).…”

The Effects of Gene Polymorphisms in Interleukin-4 and Interleukin-6 on the Susceptibility of Rheumatoid Arthritis in a Chinese Population

“…In humans the IL-4 gene has been mapped to chromosome 14q32 [34]. The IL-4 gene promoter contains a number of polymorphic loci, which were reported to influence the susceptibility of many diseases, including the IL-4-33C/T [35], IL-4-589C/T [36], and IL-4-590C/T [20, 37, 38]; especially, the genotype and allele frequencies of IL-4-590C/T were well studied and reported to be associated with many diseases, such as rheumatoid arthritis [3, 20], liver disease [37], and gastric cancer [38]. To our surprise, although the role of the genotype and allele frequencies of IL-4-590C/T in association with rheumatoid arthritis has been documented, we did not find any reports with regard to the genetic polymorphisms of IL-4-590C/T with rheumatoid arthritis in Chinese population.…”

Oct1 Is a Switchable, Bipotential Stabilizer of Repressed and Inducible Transcriptional States

“…These findings have implications for the generation of T cell memory responses and, by extension, the ability to resist infection by certain pathogens. Oct1 is associated with the expression of multiple cytokines, including Il-3, Il-5, Il-8, Il-12/23 (55)(56)(57)(58)(59)(60), and more recently Il-4 and Il-13 (61,62). Oct1 is also associated with other loci of immunological interest (e.g.…”