Dataset Information

Analysis of intergenic transcription in the human IL-4/IL-13 gene cluster.

ABSTRACT: During the differentiation of naïve CD4+ precursors to T helper 1 (Th1) or Th2 effector cells, several epigenetic changes occur in a lineage-specific manner at the IFN-gamma or IL-4/IL-13 loci. These changes result in alterations in the chromatin structure of these loci and, hence, lineage-restricted expression of the corresponding cytokines. Intergenic transcripts have recently been shown to regulate the expression of genes in the beta-globin locus; therefore, we have examined the Th2 cytokine gene cluster during human Th1/Th2 differentiation and in a transgenic mouse line containing the human IL-4/IL-13 genes for intergenic transcripts. We show for the first time that intergenic transcription of this locus is restricted to tissues and lineages in which IL-4 and IL-13 are expressed. We also show that intergenic transcription in the IL-4/IL-13 locus is up-regulated after Th2 differentiation. Furthermore, we demonstrate that the Th2 cytokines and intergenic transcripts are detectable in the thymus. We propose that intergenic transcription is tightly associated with transcriptional competence for the Th2 cytokines and may play a role in their regulation. These results support a progressive differentiation model of T cell lineage commitment.

SUBMITTER: Rogan DF

PROVIDER: S-EPMC356970 | biostudies-literature | 2004 Feb

REPOSITORIES: biostudies-literature

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Analysis of intergenic transcription in the human IL-4/IL-13 gene cluster.

Rogan David F DF Cousins David J DJ Santangelo Samantha S Ioannou Panayiotis A PA Antoniou Michael M Lee Tak H TH Staynov Dontcho Z DZ

Proceedings of the National Academy of Sciences of the United States of America 20040201 8

During the differentiation of naïve CD4+ precursors to T helper 1 (Th1) or Th2 effector cells, several epigenetic changes occur in a lineage-specific manner at the IFN-gamma or IL-4/IL-13 loci. These changes result in alterations in the chromatin structure of these loci and, hence, lineage-restricted expression of the corresponding cytokines. Intergenic transcripts have recently been shown to regulate the expression of genes in the beta-globin locus; therefore, we have examined the Th2 cytokine ...[more]

PMID: 14983029

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Project description:ObjectiveEosinophils are hallmarks in allergic type 2 inflammation and are known to release cytotoxic granule proteins that contribute to inflammation. Eosinophils develop in the bone marrow from hematopoietic stem cells and once mature, have a limited lifespan in culture, making them difficult to study ex vivo. IL-33 has increasingly been shown as a key regulator of type 2 inflammation via signaling through its receptor, ST2. The present study was conducted to detail a method of eosinophil differentiation from hematopoietic stem cells and determine the response to IL-33.MethodsCD34+ and CD14+ cells were isolated from donor apheresis cones and differentiated into eosinophils or macrophage controls, respectively. Morphologic, transcriptional and protein analyses were performed to validate this method of eosinophil differentiation. The effect of IL-33 on differentiated eosinophils was assessed using qPCR, immunofluorescence, and multiplex cytokine array.ResultsCD34 differentiated eosinophils appear morphologically similar by H&E and express eosinophil peroxidase (EPX) protein as well as the conventional eosinophil transcripts EPX, CLC, and MBP. In addition, differentiated eosinophils expressed both isoforms of the IL-33 receptor, ST2L and sST2 throughout the differentiation process. Transcript levels of both IL-33 receptors were up-regulated by treatment with IL-33 at earlier timepoints in the differentiation. These cells also expressed IL-4 and IL-13 mRNA which were up-regulated by IL-33 as well. Notably, IL-13 expression was significantly higher with IL-33 treatment compared to media control at every timepoint measured. IL-33 significantly increased cellular secretion of IL-13 protein at most timepoints throughout differentiation. IL-8, LIF, CCL1, CCL5, CCL7, and CCL8 were also significantly secreted after IL-33 stimulation.ConclusionsOur findings suggest that CD34 differentiated eosinophils are morphologically and phenotypically similar to peripheral eosinophils. The release of specific cytokines in direct response to IL-33 may contribute to the pathogenesis of type 2 inflammation and facilitates new avenues for studying eosinophils as effector cells in vitro.

Dataset Information

Analysis of intergenic transcription in the human IL-4/IL-13 gene cluster.

Publications

Analysis of intergenic transcription in the human IL-4/IL-13 gene cluster.

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