MLK4 has negative effect on TLR4 signaling.
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Seit-Nebi A, Cheng W, Xu H, Han J
MLK4 has negative effect on TLR4 signaling.
Cell Mol Immunol. 2012 Jan;9(1):27-33. doi: 10.1038/cmi.2011.15. Epub 2011 May 23.
- PubMed ID
- 21602844 [ View in PubMed]
- Abstract
The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of proinflammatory cytokines such as tumor-necrosis factor-alpha (TNF-alpha). 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-kappaB 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.