title: Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS.
abstract: 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.
authors.affiliation: Division of Immunology, Department of Translational Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Kiri
authors.initials: K
authors.lastname: Honma
authors.forename: Heiichiro
authors.initials: H
authors.lastname: Udono
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kohno
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Asako
authors.initials: A
authors.lastname: Ogawa
authors.forename: Toshitada
authors.initials: T
authors.lastname: Takemori
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumatori
authors.forename: Shoichi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Matsuyama
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Yui
mesh_terms: 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
chemical_list: D016207:Cytokines; D050835:Interferon Regulatory Factors; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; D000099218:Interferon Regulatory Factor-4