Abstract
The inositol-requiring enzyme 1α (IRE1α) is a serine-threonine kinase that plays crucial roles in activating the unfolded protein response. Studies suggest that IRE1α is activated during thymic T cell development and in effector CD8(+) T cells. However, its role in regulating T helper cell differentiation remains unknown. We find that IRE1α is up-regulated and activated upon CD4(+) T cell activation and plays an important role in promoting cytokine IL-4 production. CD4(+) T cells from IRE1α KO mice have reduced IL-4 protein expression, and this impaired IL-4 production is not due to the altered expression of Th2 lineage-specific transcription factors, such as GATA3. Instead, IL-4 mRNA stability is reduced in IRE1α KO T cells. Furthermore, treatment of T cells with an IRE1α-specific inhibitor, 4μ8C, leads to a block in IL-4, IL-5, and IL-13 production, confirming the role of IRE1α in the regulation of IL-4. This study identifies a regulatory function for IRE1α in the promotion of IL-4 in T cells.
Keywords:
Cytokine; ER Stress; IL-4; IRE1; Lymphocyte; Signal Transduction; T Cell Biology; T Cell Differentiation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Endoribonucleases / biosynthesis
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Endoribonucleases / genetics
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Endoribonucleases / immunology*
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / immunology
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GATA3 Transcription Factor / metabolism
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Interleukin-13 / biosynthesis
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Interleukin-13 / genetics
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Interleukin-13 / immunology
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Interleukin-4 / biosynthesis
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Interleukin-4 / genetics
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Interleukin-4 / immunology*
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Interleukin-5 / biosynthesis
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Interleukin-5 / genetics
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Interleukin-5 / immunology
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Mice
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Mice, Knockout
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology*
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RNA Stability / immunology
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Messenger / immunology
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Th2 Cells / cytology
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Th2 Cells / immunology*
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Th2 Cells / metabolism
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Up-Regulation / genetics
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Up-Regulation / immunology*
Substances
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Interleukin-13
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Interleukin-5
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RNA, Messenger
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Interleukin-4
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Ern1 protein, mouse
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Protein Serine-Threonine Kinases
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Endoribonucleases