TY - JOUR
T1 - Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macropages in response to LPS
AU - Honma, Kiri
AU - Udono, Heiichiro
AU - Kohno, Tomoko
AU - Yamamoto, Kazuo
AU - Ogawa, Assko
AU - Takemori, Toshitada
AU - Kumatori, Atsushi
AU - Suzuki, Shoichi
AU - Matsuyama, Toshifumi
AU - Yui, Katsuyuki
PY - 2005/11/1
Y1 - 2005/11/1
N2 - 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-α 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-κB 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.
AB - 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-α 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-κB 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.
KW - NF-κB
KW - Toll-like receptor
KW - c-Jun N-terminal kinase
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U2 - 10.1073/pnas.0504226102
DO - 10.1073/pnas.0504226102
M3 - Article
C2 - 16243976
AN - SCOPUS:27644553011
VL - 102
SP - 16001
EP - 16006
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 44
ER -