期刊
NATURE IMMUNOLOGY
卷 5, 期 1, 页码 98-103出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni1014
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- NATIONAL CANCER INSTITUTE [Z01SC010376, ZIASC010376, P30CA016672] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL070225] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI044016] Funding Source: NIH RePORTER
- NCI NIH HHS [CA16672] Funding Source: Medline
- NHLBI NIH HHS [HL070225] Funding Source: Medline
- NIAID NIH HHS [AI44016] Funding Source: Medline
Interleukin 1 receptor (IL-1R) and Toll-like receptors (TLRs) induce inflammatory genes through the complex of MyD88, IL-1R-associated protein kinase (IRAK) and tumor necrosis factor receptor-associated factor 6 (TRAF6), which is believed to function 'upstream' of the cascades of IkappaB kinase (IKK) and nuclear factor-kappaB (NF-kappaB); extracellular signal-regulated protein kinase (ERK); c-Jun N-terminal kinase (JNK); and p38 mitogen-activated protein kinase (MAPK). Here we show that MAPK-ERK kinase kinase (MEKK3) is an essential signal transducer of the MyD88-IRAK-TRAF6 complex in IL-1R-TLR4 signaling. MEKK3 forms a complex with TRAF6 in response to IL-1 and lipopolysaccharide (LPS) but not CpG, and is required for IL-1R- and TLR4-induced IL-6 production. Furthermore, MEKK3 is crucial for IL-1- and LPS-induced activation of NF-kappaB and JNK-p38 but not ERK, indicating that MAPKs are differentially activated during IL-1R-TLR4 signaling. These data demonstrate that MEKK3 is crucial for IL-1R and TLR4 signaling through the IKK-NF-kappaB and JNK-p38 MAPK pathways.
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