Interferon Regulatory Factor 4 Negatively Regulates the Production of Proinflammatory Cytokines by Macrophages in Response to LPS
A member of the IFN regulatory factor (IRF) family of transcription factors, IRF-4 is expressed in lymphocytes and macrophage/dendritic cells. Studies using IRF-4-deficient mice have revealed the critical roles of IRF-4 in lymphocyte responses. However, the role of IRF-4 in innate immune responses i...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2005-11, Vol.102 (44), p.16001-16006 |
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Sprache: | eng |
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Zusammenfassung: | A member of the IFN regulatory factor (IRF) family of transcription factors, IRF-4 is expressed in lymphocytes and macrophage/dendritic cells. Studies using IRF-4-deficient mice have revealed the critical roles of IRF-4 in lymphocyte responses. However, the role of IRF-4 in innate immune responses is not clearly understood. Here, we demonstrate that IRF-4 negatively regulates the production of proinflammatory cytokines by macrophages in response to Toll-like receptor (TLR) stimulation. Mice lacking IRF-4 are sensitive to LPS-induced shock, and their macrophages produce high levels of proinflammatory cytokines, including$TNF-\alpha$and IL-6, in response to TLR ligands. The inhibitory role of IRF-4 in response to TLR stimulation was confirmed by the down-regulation of IRF-4 expression in normal macrophages by using the small interfering RNA technique and by the overexpression of IRF-4 in macrophage line RAW264.7. Activation of the important signaling pathways for cytokine production, NF-κ B and JNK (c-Jun N-terminal kinase), was enhanced after LPS stimulation in$IRF-4^{-/-}$macrophages. These results imply that IRF-4 negatively regulates TLR signaling and is inhibitory to the production of proinflammatory cytokines in response to TLR stimulation. |
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ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0504226102 |