Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macropages in response to LPS

Kiri Honma, Heiichiro Udono, Tomoko Kohno, Kazuo Yamamoto, Assko Ogawa, Toshitada Takemori, Atsushi Kumatori, Shoichi Suzuki, Toshifumi Matsuyama, Katsuyuki Yui

Research output: Contribution to journalArticle

91 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)16001-16006
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number44
DOIs
Publication statusPublished - Nov 1 2005
Externally publishedYes

Keywords

  • NF-κB
  • Toll-like receptor
  • c-Jun N-terminal kinase

ASJC Scopus subject areas

  • General

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