C4b‐binding protein negatively regulates TLR4/MD‐2 response but not TLR3 response

• Published in: FEBS letters Vol. 591; no. 12; pp. 1732 - 1741
• Main Authors: Morita, Naoko, Yamazaki, Tatsuya, Murakami, Yusuke, Fukui, Ryutaro, Yamai, Ikuko, Ichimonji, Isao, Nakashima, Akina, Nagaoka, Fumiaki, Takagi, Hidekazu, Miyake, Kensuke, Akashi‐Takamura, Sachiko
• Format: Journal Article
• Language: English
• Published: England 01.06.2017
• Subjects: Animals; C4b‐binding protein; Cytokines - agonists; Cytokines - antagonists & inhibitors; Cytokines - metabolism; Down-Regulation - drug effects; Female; HEK293 Cells; Histocompatibility Antigens - chemistry; Histocompatibility Antigens - genetics; Histocompatibility Antigens - metabolism; Humans; Ligands; Lipid A - toxicity; lipopolysaccharide; Lipopolysaccharides - toxicity; Lymphocyte Antigen 96 - agonists; Lymphocyte Antigen 96 - antagonists & inhibitors; Lymphocyte Antigen 96 - genetics; Lymphocyte Antigen 96 - metabolism; Macrophage Activation - drug effects; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Knockout; NF-kappa B - agonists; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; RAW 264.7 Cells; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Signal Transduction - drug effects; Toll-Like Receptor 3 - chemistry; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - metabolism; Toll-Like Receptor 4 - agonists; Toll-Like Receptor 4 - antagonists & inhibitors; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; toll‐like receptor; lipopolysaccharide; toll-like receptor; C4b-binding protein
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1002/1873-3468.12693

Recently, we reported a novel function for C4b‐binding protein (C4BP) in inhibiting the toll‐like receptor (TLR)1/2 response by interacting with TLR2. TLRs share a common structure; hence, we examined the effect of C4BP on activation of other TLRs—TLR4 and TLR3. The results of immunoprecipitation assays suggest that C4BP interacts with TLR4/MD‐2 but not TLR3. C4BP inhibits TLR4/MD‐2‐mediated, but not TLR3‐mediated, proinflammatory cytokine production and nuclear factor (NF)‐κB signaling. C4BP‐deficient mice show increased interleukin (IL)‐6 production in response to the TLR4/MD‐2 ligand. A competition assay revealed that C4BP prevents an interaction between TLR4/MD‐2 and its ligand. These findings indicate that C4BP binds to cell surface TLRs and inhibits the TLR–TLR ligand interaction, thereby inhibiting TLR activation.