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 IκB kinase (IKK) and nuclear factor-κB (NF-κB); 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-κB 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-κB and JNK–p38 MAPK pathways.

*Note: In the version of this article originally published online, the third author's name was incorrect. The correct author name should be Yong Lin. This error has been corrected for the HTML and print versions of this article.