title: IRF4 regulates IL-10 gene expression in CD4(+) T cells through differential nuclear translocation.
abstract: CD4(+) T cells play critical roles in the generation of protective immunity against a variety of pathogens. The main two types of effector CD4(+) T cells, Th1 and Th2 are characterized by their ability to produce signature cytokines. Among them, IL-10 is a multi-functional cytokine that plays a crucial role in maintaining the balance between immunity and tolerance. Although IL-10 is produced by both differentiated primary Th1 and Th2 cells, Th2 cells produce much higher levels of IL-10 upon stimulation. However, little information is available on the molecular mechanisms of IL-10 gene regulation at the transcriptional level. Interferon regulatory factor IRF4 is a member of the IRF family of transcription factors and plays critical roles in the development of CD4(+) T cells into Th2 cells. In this present study, we elucidate the underlying mechanism of IRF4 mediated IL-10 gene transcription in primary CD4(+) T cells. Th2 specific binding of IRF4 to the IRF4 responsive elements in IL-10 locus potentiated IL-10 expression in Th2 cells. Knockdown of IRF4 by siRNA decreased IL-10 expression level in Th2 cells. Nuclear translocation of IRF4 was much higher in Th2 cells upon stimulation, which contribute to maintain IL-10(high) phenotype of Th2 cells. Collectively, our results suggest that stimulation driven quantitative differences of IRF4 in the nucleus and its binding to IL-10 regulatory elements are crucial mechanisms to induce IL-10(high) gene expression in Th2 cells.
authors: School of Life Sciences and Immune Synapse Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors: Choong-Gu
authors: CG
authors: Lee
authors: Won
authors: W
authors: Hwang
authors: Ki-Eun
authors: KE
authors: Maeng
authors: Ho-Keun
authors: HK
authors: Kwon
authors: Jae-Seon
authors: JS
authors: So
authors: Anupama
authors: A
authors: Sahoo
authors: Sung Haeng
authors: SH
authors: Lee
authors: Zee Yong
authors: ZY
authors: Park
authors: Sin-Hyeog
authors: SH
authors: Im
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms; D018418:Th2 Cells / Q000276:immunology / Q000502:physiology*; D014158:Transcription, Genetic; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D016753:Interleukin-10; D012313:RNA; D034741:RNA, Small Interfering; D000099218:Interferon Regulatory Factor-4; C556062:IL10 protein, mouse