IFN Regulatory Factor 4 Regulates the Expression of a Subset of Th2 Cytokines

Th2 cells can be subdivided into subpopulations depending on the level of a cytokine and the subsets of cytokines they produce. We have recently identified the ETS family transcription factor PU.1 as regulating heterogeneity in Th2 populations. To define additional factors that might contribute to T...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2009-08, Vol.183 (3), p.1598-1606
Main Authors: Ahyi, Ayele-Nati N, Chang, Hua-Chen, Dent, Alexander L, Nutt, Stephen L, Kaplan, Mark H
Format: Article
Language:English
Subjects:
Animals
Cytokines - biosynthesis
Gene Expression Regulation - immunology
Interferon Regulatory Factors - physiology
Interleukin-10 - genetics
Mice
Protein Binding
Proto-Oncogene Proteins - metabolism
Th2 Cells - immunology
Trans-Activators - metabolism
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Summary:Th2 cells can be subdivided into subpopulations depending on the level of a cytokine and the subsets of cytokines they produce. We have recently identified the ETS family transcription factor PU.1 as regulating heterogeneity in Th2 populations. To define additional factors that might contribute to Th2 heterogeneity, we examined the PU.1 interacting protein IFN-regulatory factor (IRF)4. When Th2 cells are separated based on levels of IL-10 secretion, IRF4 expression segregates into the subset of Th2 cells expressing high levels of IL-10. Infection of total Th2 cells, and IL-10 nonsecreting cells, with retrovirus-expressing IRF4, resulted in increased IL-4 and IL-10 expression, no change in IL-5 or IL-13 production and decreased Il9 transcription. Transfection of an IRF4-specific small interfering RNA into Th2 cells decreases IL-10 production. IRF4 directly binds the Il10 gene as evidenced by chromatin immunoprecipitation assay, and regulates Il10 control elements in a reporter assay. IRF4 interacts with PU.1, and in PU.1-deficient T cells there was an increase in IRF4 binding to the Il10 gene, and in the ability of IRF4 to induce IL-10 production compared with wild-type cells and Il10 promoter activity in a reporter assay. Further heterogeneity of IRF4 expression was observed in Th2 cells analyzed for expression of multiple Th2 cytokines. Thus, IRF4 promotes the expression of a subset of Th2 cytokines and contributes to Th2 heterogeneity.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.0803302