Published online August 27, 2007
doi:10.1084/jem.20070183
The Journal of Experimental Medicine, Vol. 204, No. 9, 2233-2239
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Yamamoto et al.
Enhanced TLR-mediated NF-IL6–dependent gene expression by Trib1 deficiency
Masahiro Yamamoto1,3,
Satoshi Uematsu1,
Toru Okamoto2,
Yoshiharu Matsuura2,
Shintaro Sato4,
Himanshu Kumar1,
Takashi Satoh1,4,
Tatsuya Saitoh1,
Kiyoshi Takeda3,5,
Ken J. Ishii4,
Osamu Takeuchi1,4,
Taro Kawai1,4, and
Shizuo Akira1,4
1 Department of Host Defense and 2 Department of Molecular Virology, Research Institute for Microbial Diseases and 3 Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
4 Exploratory Research for Advanced Technology, Japan Science and Technology Corporation, Suita, Osaka, 565-0871, Japan
5 Department of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
CORRESPONDENCE Shizuo Akira: sakira{at}biken.osaka-u.ac.jp
Toll-like receptors (TLRs) recognize a variety of microbial components and mediate downstream signal transduction pathways that culminate in the activation of nuclear factor 
B (NF-B) and mitogen-activated protein (MAP) kinases. Trib1 is reportedly involved in the regulation of NF-B 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-B was normal. Trib1 was found to associate with NF-IL6 (also known as CCAAT/enhancer-binding protein ß). 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.
Abbreviations used: 24p3, lipocalin-2; BLP, bacterial lipoprotein; C/EBP, CCAAT/enhancer-binding protein; Jnk, c-Jun N-terminal kinase; MALP-2, macrophage-activating lipopeptide–2; MAP, mitogen-activated protein; mPGES, prostaglandin E synthase; TLR, Toll-like receptor.
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