Enhanced TLR-mediated NF-IL6 dependent gene expression by Trib1 deficiency.
Toll-like receptors (TLRs) recognize a variety of microbial components and mediate downstream signal transduction pathways that culminate in the activation of nuclear factor kappaB (NF-kappaB) and mitogen-activated protein (MAP) kinases. Trib1 is reportedly involved in the regulation of NF-kappaB and MAP kinases, as well as gene expression in vitro. To clarify the physiological function of Trib1 in TLR-mediated responses, we generated Trib1-deficient mice by gene targeting. Microarray analysis showed that Trib1-deficient macrophages exhibited a dysregulated expression pattern of lipopolysaccharide-inducible genes, whereas TLR-mediated activation of MAP kinases and NF-kappaB was normal. Trib1 was found to associate with NF-IL6 (also known as CCAAT/enhancer-binding protein beta). NF-IL6-deficient cells showed opposite phenotypes to those in Trib1-deficient cells in terms of TLR-mediated responses. Moreover, overexpression of Trib1 inhibited NF-IL6-dependent gene expression by down-regulating NF-IL6 protein expression. In contrast, Trib1-deficient cells exhibited augmented NF-IL6 DNA-binding activities with increased amounts of NF-IL6 proteins. These results demonstrate that Trib1 is a negative regulator of NF-IL6 protein expression and modulates NF-IL6-dependent gene expression in TLR-mediated signaling.
Yamamoto
Masahiro
M
Department of Host Defense and Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Uematsu
Satoshi
S
Okamoto
Toru
T
Matsuura
Yoshiharu
Y
Sato
Shintaro
S
Kumar
Himanshu
H
Satoh
Takashi
T
Saitoh
Tatsuya
T
Takeda
Kiyoshi
K
Ishii
Ken J
KJ
Takeuchi
Osamu
O
Kawai
Taro
T
Akira
Shizuo
S
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D007109:Immunity; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000037:antagonists & inhibitors; D051193:Toll-Like Receptors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
D022782:CCAAT-Enhancer-Binding Protein-beta; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; C523598:Trib1 protein, mouse; D017346:Protein Serine-Threonine Kinases