T-cell subset-specific expression of the IL-4 gene is regulated by a silencer element and STAT6

Abstract

During development of CD4+ T lymphocytes in the periphery, differential expression of cytokine genes, such as those of interleukin (IL)‐2 and IL‐4, occurs in distinct T‐cell subsets. IL‐4 is a cytokine produced by T‐helper 2 (Th2) cells, and the IL‐4 receptor (IL‐4R)‐mediated signaling pathway is thought to be required for commitment to the Th2 phenotype. However, the molecular basis for development of the Th subset‐specific production of IL‐4 remains unclear. We demonstrate here that the IL‐4 promoter is functional in Th1 and B cells which do not normally form IL‐4 transcripts as well as in IL‐4‐producing T cells. Based on studies of the effect of several different upstream and downstream regions of the IL‐4 gene on IL‐4 promoter activity, a Th1‐specific IL‐4 silencer element was identified in the 3′‐untranslated region. The silencer region contained a consensus sequence for a transcriptional factor that is normally regulated by the IL‐4 R signaling pathway, STAT6. Nuclear expression of STAT6 protein, which was shown to bind to the silencer region, was observed in Th2 cells but not in Th1 cells. Deletion of the STAT6‐binding site from the silencer region and inhibition of STAT6 function resulted in the appearance of silencing function even in Th2 cells. These results provide evidence that the silencer element, and the binding of STAT6 to this element, play a permissive role in determining the commitment into Th2 phenotype.

Class II Major Histocompatibility Complex Transactivator (CIITA) Inhibits Matrix Metalloproteinase-9 Gene Expression

“…Indeed, in previous studies (17,18), CIITA was shown to inhibit the expression of both IL-4 and Fas-L, two genes that are regulated by the transcription factor NFAT. Moreover, both CIITA and NFAT bind to the CH3 domain of CBP (32,(41)(42)(43). Although we have not identified the transcription factor(s) affected by CIITA-CBP interactions, several possibilities exist.…”

Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naïve vs. effector/memory CD4+T cells

“…However, IL-4 expression is controlled not only by the IL-4 promoter, but by several other regulatory elements, including enhancers, silencers, and locus control regions, which become targets of transcription factors and chromatin-remodeling factors (3,4). There are IRF-binding sites within the silencer region (35). Therefore, IRF-4 may affect not only promoter activity of the target genes, but also the chromatin environment of the target genes in regulating gene expression (36).…”

Role of Mast Cells and Basophils in IgE Responses and in Allergic Airway Hyperresponsiveness

“…Mice expressing the human DTR under the control of IE element (for Mas-TRECK) and 39UTR element (for Bas-TRECK) in the Il4 gene locus were generated by a Tg strategy. The basic pIL-4 construct was made by insertion of the 59enhancer (2863 to 25448; the start codon is defined as 0) (22) and the IL-4 promoter from position 264 to 2827. The human DTR fragment was isolated from the DTR/pMS7 vector (provided by Dr. M. Tanaka, Research Center for Allergy and Immunology, the Institute of Physical and Chemical Research) and inserted into the basic pIL-4 construct.…”