Open AccessMLK4 has negative effect on TLR4 signaling
Author(s) -
Alim S. Seit-Nebi,
Wei Cheng,
Hong Xu,
Jiahuai Han
Publication year - 2011
Publication title -
cellular and molecular immunology/cellular and molecular immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.5
H-Index - 81
eISSN - 2042-0226
pISSN - 1672-7681
DOI - 10.1038/cmi.2011.15
Subject(s) - map kinase kinase kinase , tlr4 , microbiology and biotechnology , proinflammatory cytokine , p38 mitogen activated protein kinases , signal transduction , mitogen activated protein kinase kinase , mapk/erk pathway , kinase , protein kinase a , biology , tumor necrosis factor alpha , ask1 , cyclin dependent kinase 9 , cancer research , chemistry , immunology , inflammation
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.