Journal Article

MLK4 has negative effect on TLR4 signaling

Han, Jiahuai, Xu, Hong, Seit-Nebi, Alim, Cheng, Wei

2012

Overview

The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of proinflammatory cytokines such as tumor-necrosis factor-α (TNF-α). The TNF production is mediated by a series of signaling events and subsequent transcriptional and post-transcriptional activation of the TNF gene. Termination of TLR-mediated cellular signaling is also important for a proper immunoresponse, since sustained cytokine expression can result in immune disorders. Here we identified that mixed-lineage kinase (MLK) 4 is a TLR4-interacting protein. Unlike previously characterized MLK group members, MLK4 cannot act as a mitogen-activated protein kinase kinase kinase (MAP3K) to mediate c-Jun N-terminal kinase (JNK), p38 or extracellular signal-regulated kinase (ERK) activation. Rather, MLK4 appears to be able to inhibit lipopolysaccharide (LPS)-induced activation of the JNK or ERK pathways, but does not have effect on LPS-induced p38 or NF-κB activation. The LPS-induced TNF production in MLK4 knockdown and overexpression cells were also increased and reduced, respectively. These data demonstrate that MLK4 is a negative regulator of TLR4 signaling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Antibodies / Biomedical and Life Sciences / Biomedicine / c-Jun amino-terminal kinase / c-Jun protein / Cytokines / Data processing / Enzyme Activation - drug effects / Enzyme Activation - genetics / Enzyme Activation - immunology / Extracellular signal-regulated kinase / Gene Knockdown Techniques / HEK293 Cells / Humans / Immunology / Inflammation / JNK protein / Kinases / Lipopolysaccharides / Lipopolysaccharides - pharmacology / Macrophages / MAP kinase / MAP Kinase Kinase 4 - genetics / MAP Kinase Kinase 4 - immunology / MAP Kinase Kinase Kinases - genetics / MAP Kinase Kinase Kinases - immunology / MAP Kinase Signaling System - drug effects / MAP Kinase Signaling System - immunology / Medical Microbiology / Metabolic pathways / Mice / Microbiology / NF- Kappa B protein / NF-κB protein / p38 Mitogen-Activated Protein Kinases - genetics / p38 Mitogen-Activated Protein Kinases - immunology / Post-transcription / Protein kinase / research-article / Signal transduction / TLR4 protein / Toll-Like Receptor 4 - genetics / Toll-Like Receptor 4 - immunology / Toll-like receptors / Transcription activation / Transcription factors / Tumor necrosis factor- alpha / Tumor necrosis factor-α / Tumors / Vaccine