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Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3

Nature Immunology volume 5, pages 98–103 (2004)Cite this article

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Abstract

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.

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Figure 1: IL-6 expression in MEFs requires MEKK3 but not MEKK2.
Figure 2: IL-6 induction in by IL-1, LPS and CpG.
Figure 3: MEKK3 is a downstream signal transducer of MyD88, IRAK1 and TRAF6 in the IL-1R signaling pathway.
Figure 4: Activation of JNK, ERK and p38 MAPK in wild-type and Mekk3−/− MEFs.

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  • 15 December 2003

    appended aop PDF with corrigendum (will be corrected for print issue), and placed footnote in SGML at abstract

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Acknowledgements

We thank R. Medzhitov, Y. Liu and Y.J. Liu for suggestions and critically reading the manuscript; M. Goode for editing the manuscript; X. Li for sharing plasmids; and B. Wang for technical assistance. Supported partially by the National Institutes of Health (AI44016 and HL070225) and Texas High Education (ARP; both to B.S.), by the Department of Defense (DAMD17-02-0449; Q.H.) and by a Cancer Center Core grant (CA16672; M.D. Anderson Cancer Center).

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Authors and Affiliations

  1. Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, USA

    Qiaojia Huang, Jianhua Yang, Christopher Walker, Jinke Cheng & Bing Su

  2. Department of Cell and Cancer Biology, National Cancer Institute, Bethesda, 20892, Maryland, USA

    Yong Lin & Zheng-gang Liu

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Correspondence to Bing Su.

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Huang, Q., Yang, J., Lin, Y. et al. Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nat Immunol 5, 98–103 (2004). https://doi.org/10.1038/ni1014

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