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

  title={Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3},
  author={Qiaojia Huang and Jianhua Yang and Yong Loo Lin and Christopher Walker and Jinke Cheng and Zheng-Gang Liu and Bing Su},
  journal={Nature Immunology},
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… 

Modulation of Toll–interleukin 1 receptor mediated signaling

Genetic and biochemical studies reveal that IL-1R uses adaptor molecule MyD88 to mediate a very complex pathway, involving a cascade of kinases organized by multiple adapter molecules into signaling complexes, leading to activation of the transcription factor NFκB.

SIGIRR Inhibits Interleukin-1 Receptor- and Toll-like Receptor 4-mediated Signaling through Different Mechanisms*

Results indicate that SIGIRR inhibits IL-1 and LPS signaling pathways through differential mechanisms.

IRAK-4 Kinase Activity Is Required for Interleukin-1 (IL-1) Receptor- and Toll-like Receptor 7-mediated Signaling and Gene Expression*

The results suggest that IRAK-4 kinase activity plays a critical role in IL-1 receptor (IL-1R)/TLR7-mediated induction of inflammatory responses.

CaMKII promotes TLR-triggered proinflammatory cytokine and type I interferon production by directly binding and activating TAK1 and IRF3 in macrophages.

It is demonstrated that TLR 4, 9, and 3 ligands markedly induce intracellular calcium fluxes and activate CaMKII-alpha in macrophages, and in turn promotes both myeloid differentiating factor 88 and Toll/IL-1 receptor domain-containing adaptor protein-inducing IFN-beta-dependent inflammatory responses by directly activating TAK1 and IRF3.

Interleukin-8 Induces Nuclear Transcription Factor-κB through a TRAF6-dependent Pathway*

The data suggest that IL-8-induced NF-κB activation proceeds through a TRAF2-independent but TRAF6-dependent pathway, followed by recruitment of IRAK and activation of IKK andactivation of NF-σκB and its dependent genes may be one of the pathways of IL- 8-induced inflammation and angiogenesis.

Mitogen-activated protein kinase phosphatase-1 (MKP-1): a critical regulator of innate immune responses

Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a nuclear-localized dual-specificity phosphat enzyme that is induced by TLR stimulation in macrophages, resulting in the attenuation of TLR-triggered production of pro-inflammatory cytokines and other inflammatory mediators.

Phosphatidylinositol 4-Phosphate 5-Kinase α Facilitates Toll-like Receptor 4-mediated Microglial Inflammation through Regulation of the Toll/Interleukin-1 Receptor Domain-containing Adaptor Protein (TIRAP) Location*

The results suggest that PIP5Kα promotes TLR4-associated microglial inflammation by mediating PIP2-dependent recruitment of TIRAP to the plasma membrane.

Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFκB Activation Pathways Bifurcate at IL-1 Receptor-associated Kinase Modification*

Through the study of these IRAK modification mutants, two parallel IL-1-mediated signaling pathways for NFκB activation, TAK1-dependent and MEKK3-dependent, respectively are uncovered and provide significant insight to the further understanding of NFκBs activation pathways.



The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense

The interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily plays a central role in inflammation and the host response to bacterial infection, and is evolutionarily conserved and a critical determinant of innate immune and inflammatory responses.

The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway

It is shown that the MAPKK kinase TAK1 acts upstream of NIK in the IL-1-activated signalling pathway and that TAK 1 associates with TRAF6 during IL- 1 signalling, which indicates that Taker1 links TRAf6 to the NIK–IKK cascade in theIL-1 signalling pathway.

Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain.

Oligomerization of the TRAF2 effector domain results in specific binding to MEKK1, a protein kinase capable of JNK, p38, and IKK activation, and induction of TNF-alpha and IL-1 responsive genes.

MAP3K-related kinase involved in NF-KB induction by TNF, CD95 and IL-1

The findings indicate that NIK participates in an NF-KB-inducing signalling cascade common to receptors of the TNF/NGF family and to the interleukin-1 type-I receptor.

The essential role of MEKK3 in TNF-induced NF-κB activation

It is found that MEKK3 plays a critical role in TNF-induced NF-κB activation and functions downstream of receptor-interacting protein (RIP) and TNF receptor– associated factor 2.

TICAM-1, an adaptor molecule that participates in Toll-like receptor 3–mediated interferon-β induction

This work has identified an alternative adaptor, designated Toll-interleukin 1 receptor domain (TIR)-containing adaptor molecule (TICAM)-1, that can physically bind the TIR domain of TLR3 and activate the IFN-β promoter in response to poly(I):poly(C).

Cutting Edge: A Novel Toll/IL-1 Receptor Domain-Containing Adapter That Preferentially Activates the IFN-β Promoter in the Toll-Like Receptor Signaling1

Findings suggest that TRIF is involved in the TLR signaling, particularly in the MyD88-independent pathway.

TAK1 is a ubiquitin-dependent kinase of MKK and IKK

The purification and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism, indicate that ubiquitination has an important regulatory role in stress response pathways, including those of IKK and JNK.

TAB2 Is Essential for Prevention of Apoptosis in Fetal Liver but Not for Interleukin-1 Signaling

It is demonstrated that TAB2 is essential for embryonic development through prevention of liver apoptosis but not for the IL-1 receptor-mediated signaling pathway.