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

Yao, Jinrong; Kim, Tae Whan; Qin, Jinzhong; Jiang, Zhengfan; Qian, Youcun; Xiao, Hui; Lu, Yi; Wen, Qian; Gulen, Muhammet F.; Sizemore, Nywana; DiDonato, Joseph; Sato, Shintaro; Akira, Shizuo; Su, Bing; Li, Xiaoxia

doi:10.1074/jbc.m609039200

Cited by 105 publications

(132 citation statements)

References 49 publications

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“…Likewise, our observations are in keeping with the previous demonstration that TAK1 is necessary for MEKK3 activation (48). Conversely, other investigators have reported that MEKK3 activation can also occur independently of TAK1 (49,50). These various groups all agree, however, on the fact that TAK1 and MEKK3 jointly activate NF-kB using separate, complementary pathways (48)(49)(50).…”

Section: Discussionsupporting

confidence: 92%

“…Clearly, other conditions are needed, which remain to be identified. Finally, the manner in which MEKK3 affects NF-kB activity was reported to involve the phosphorylation of IKKg (49,50). In keeping with this view, we observed that fMLF (but not GM-CSF) elicited not only MEKK3 activity, but also a modest and belated phosphorylation of IKKg.…”

Section: Discussionsupporting

confidence: 86%

“…Conversely, other investigators have reported that MEKK3 activation can also occur independently of TAK1 (49,50). These various groups all agree, however, on the fact that TAK1 and MEKK3 jointly activate NF-kB using separate, complementary pathways (48)(49)(50). In this regard, results obtained in this study with fMLF-stimulated neutrophils show that the concurrent activation of MEKK1, MEKK3, and TAK1 is not sufficient per se to result in the activation of the IKKb/NF-kB cascade.…”

Section: Discussionsupporting

confidence: 66%

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Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses

Sylvain-Prévost

Ear

Simard

et al. 2015

The Journal of Immunology

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The MAP3 kinase, TAK1, is known to act upstream of IKK and MAPK cascades in several cell types, and is typically activated in response to cytokines (e.g., TNF, IL-1) and TLR ligands. In this article, we report that in human neutrophils, TAK1 can also be activated by different classes of inflammatory stimuli, namely, chemoattractants and growth factors. After stimulation with such agents, TAK1 becomes rapidly and transiently activated. Blocking TAK1 kinase activity with a highly selective inhibitor (5z-7-oxozeaenol) attenuated the inducible phosphorylation of ERK occurring in response to these stimuli but had little or no effect on that of p38 MAPK or PI3K. Inhibition of TAK1 also impaired MEKK3 (but not MEKK1) activation by fMLF. Moreover, both TAK1 and the MEK/ERK module were found to influence inflammatory cytokine expression and release in fMLF- and GM-CSF–activated neutrophils, whereas the PI3K pathway influenced this response independently of TAK1. Besides cytokine production, other responses were found to be under TAK1 control in neutrophils stimulated with chemoattractants and/or GM-CSF, namely, delayed apoptosis and leukotriene biosynthesis. Our data further emphasize the central role of TAK1 in controlling signaling cascades and functional responses in primary neutrophils, making it a promising target for therapeutic intervention in view of the foremost role of neutrophils in several chronic inflammatory conditions.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 66%

See 1 more Smart Citation

Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses

Sylvain-Prévost

Ear

Simard

et al. 2015

The Journal of Immunology

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“…In addition, IL-1-induced IkBa phosphorylation is only completely abolished when both TAK1 and MEKK3 are impaired [63]. In this context, Yao et al proposed the existence of two independent signaling pathways to NF-kB upon IL-1 stimulation.…”

Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 99%

“…The TAK1-independent, MEKK3-dependent pathway involves IKKg phosphorylation and IKKa activation. Remarkably, the latter results in NF-kB activation through IkBa phosphorylation and dissociation from NF-kB, but is not associated with IkBa degradation [63]. Review Article 2969 [76]).…”

Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 99%

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

Verstrepen

Bekaert

Chau

et al. 2008

Cell. Mol. Life Sci.

398

297

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Abstract. Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kB (NF-kB). TLR, IL-1R and TNF-R signaling to NF-kB converge on a common IkB kinase complex that phosphorylates the NF-kB inhibitory protein IkBa. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-kB signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways.Keywords. Toll-like receptor 4, interleukin-1, tumor necrosis factor, NF-kB, signal transduction. NF-kB, does it still need to be introduced?Nuclear factor kB (NF-kB) is the generic name of a family of transcription factors that regulate the expression of a large number of genes involved in immune and inflammatory responses, as well as in cell survival, cell proliferation and cell differentiation. NFkB transcription factors are activated in response to various stimuli, including cytokines, infectious agents, injury and other stressful conditions requiring rapid reprogramming of gene expression. Inappropriate activation of the NF-kB signaling pathway is implicated in the pathogenesis of chronic inflammation and autoimmunity, certain hereditary disorders and various cancers. In mammals, the NF-kB family consists of five proteins sharing a highly conserved Rel homology domain: c-Rel, RelB, p65 (= RelA), p105 (= NF-kB1) and p100 (=NF-kB2). The first three contain Cterminal transactivation domains, while the others share a long C-terminal domain with multiple copies of ankyrin repeats, which inhibit their activation.

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Biomechanical signals inhibit IKK activity to attenuate NF‐κB transcription activity in inflamed chondrocytes

Dossumbekova¹,

Anghelina²,

Madhavan³

et al. 2007

Arthritis & Rheumatism

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Objective. While the effects of biomechanical signals in the form of joint movement and exercise are known to be beneficial to inflamed joints, limited information is available regarding the intracellular mechanisms of their actions. This study was undertaken to examine the intracellular mechanisms by which biomechanical signals suppress proinflammatory gene induction by the interleukin-1-␤ (IL-1␤)-induced NF-B signaling cascade in articular chondrocytes.Methods. Primary rat articular chondrocytes were exposed to biomechanical signals in the form of cyclic tensile strain, and the effects on the NF-B signaling cascade were examined by Western blot analysis, real-time polymerase chain reaction, and immunofluorescence.Results. Cyclic tensile strain rapidly inhibited the IL-1␤-induced nuclear translocation of NF-B, but not its IL-1␤-induced phosphorylation at serine 276 and serine 536, which are necessary for its transactivation and transcriptional efficacy, respectively. Examination of upstream events revealed that cyclic tensile strain also inhibited the cytoplasmic protein degradation of IB␤ and IB␣, as well as repressed their gene transcription. Additionally, cyclic tensile strain induced a rapid nuclear translocation of IB␣ to potentially prevent NF-B binding to DNA. Furthermore, the inhibition of IL-1␤-induced degradation of IB by cyclic tensile strain was mediated by down-regulation of IB kinase activity.Conclusion. These results indicate that the signals generated by cyclic tensile strain act at multiple sites within the NF-B signaling cascade to inhibit IL-1␤-induced proinflammatory gene induction. Taken together, these findings provide insight into how biomechanical signals regulate and reduce inflammation, and underscore their potential in enhancing the ability of chondrocytes to curb inflammation in diseased joints.

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

Cited by 105 publications

References 49 publications

Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses

Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

Biomechanical signals inhibit IKK activity to attenuate NF‐κB transcription activity in inflamed chondrocytes

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