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 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-kappaB 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.
Honma
Kiri
K
Division of Immunology, Department of Translational Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Udono
Heiichiro
H
Kohno
Tomoko
T
Yamamoto
Kazuo
K
Ogawa
Asako
A
Takemori
Toshitada
T
Kumatori
Atsushi
A
Suzuki
Shoichi
S
Matsuyama
Toshifumi
T
Yui
Katsuyuki
K
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
D016207:Cytokines; D050835:Interferon Regulatory Factors; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; D000099218:Interferon Regulatory Factor-4