title: MLK4 has negative effect on TLR4 signaling.
abstract: 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.
authors: Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, China.
authors: Alim
authors: A
authors: Seit-Nebi
authors: Wei
authors: W
authors: Cheng
authors: Hong
authors: H
authors: Xu
authors: Jiahuai
authors: J
authors: Han
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