The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of proinflammatory cytokines such as tumor-necrosisfactor-a (TNF-a). The TNF production is mediated by a series of signaling events and ...The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of proinflammatory cytokines such as tumor-necrosisfactor-a (TNF-a). The TNF production is mediated by a series of signaling events and subsequent transcriptional andpost-transcriptional activation of the TNF gene. Termination of TLR-mediated cellular signaling is also important for a properimmunoresponse, 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-activatedprotein 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, butdoes not have effect on LPS-induced p38 or NF-kB activation. The LPS-induced TNF production in MLK4 knockdown andoverexpression cells were also increased and reduced, respectively. These data demonstrate that MLK4 is a negative regulator of TLR4signaling.展开更多
基金grants from NSF China(30830092,30921005,91029304 and 81061160512)973 Program(2009CB522200)and National Institutes of Health(AI41637 and AI68896).
文摘The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of proinflammatory cytokines such as tumor-necrosisfactor-a (TNF-a). The TNF production is mediated by a series of signaling events and subsequent transcriptional andpost-transcriptional activation of the TNF gene. Termination of TLR-mediated cellular signaling is also important for a properimmunoresponse, 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-activatedprotein 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, butdoes not have effect on LPS-induced p38 or NF-kB activation. The LPS-induced TNF production in MLK4 knockdown andoverexpression cells were also increased and reduced, respectively. These data demonstrate that MLK4 is a negative regulator of TLR4signaling.
