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 kappa B ( NF-kappa B) and mitogen-activated protein ( MAP) kinases. Trib1 is reportedly involved in the regulation of NF-kappa 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-kappa B 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.