TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cells

Kaiser, Frank J.; Cook, Dorthe; Παπουτσοπουλου, Σταματια; Rajsbaum, Ricardo; Wu, Xuemei; Yang, Haiying; Grant, Susan; Ricciardi‐Castagnoli, Paola; Tsichlis, Philip N.; Ley, Steven C.; O’Garra, Anne

doi:10.1084/jem.20091059

Cited by 150 publications

(228 citation statements)

References 43 publications

(97 reference statements)

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“…We next decided to determine how Cot/tpl2 regulates the expression of other genes involved in the macrophage response to LPS stimulation. In agreement with previous data [39,40], Cot/tpl2 repressed IFN-b and IL-12 p40 transcripts levels in LPS-activated macrophages (Supporting Information Fig. S4), furthermore LPS-stimulated Cot/tpl2 KO BMDMs showed enhanced IFN-g, CCL5 and CXCL-10 while decreased CXCL-1 mRNA expression levels versus their LPSstimulated WT counterparts (Supporting Information Fig.…”

Section: Resultssupporting

confidence: 92%

“…2A). A similar JNK and p38a phosphorylation state was observed between WT and Cot/tpl2 KO BMDMs within the first 40 min following LPS stimulation, in accordance with earlier studies [17,36,39]. However, p38a and JNK phosphorylation were sustained for longer in LPS-stimulated Cot/tpl2 KO BMDMs versus WT BMDMs.…”

Section: Increased P38a and Jnk Phosphorylation And Impaired Ijba Recsupporting

confidence: 90%

“…Nevertheless, Cot/tpl2 modulates the expression of other genes in TLR-activated macrophages independently of its control over Akt phosphorylation. The increased IFN-b production in LPS-stimulated Cot/tpl2-deficient BMDMs is reversed by transfection with c-Fos [39], an Erk1/2-dependent transcription factor. In addition, here we show that complete inhibition of Erk1/2 activity, but not the complete inhibition of Akt phosphorylation, increases IRF1 expression levels in LPS-stimulated WT BMDMs.…”

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confidence: 97%

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Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

et al. 2011

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LPS stimulation activates IKK and different MAP kinase pathways, as well as the PI3K-AktmTOR-p70 S6k pathway, a negative regulator of these MyD88-dependent intracellular signals. Here, we show that Cot/tpl2, a MAP3K responsible for the activation of the MKK1-Erk1/2, controls P-Ser473 Akt and P-Thr389 p70 S6k phosphorylation in LPS-stimulated macrophages. Analysis of the intracellular signalling in Cot/tpl2 KO macrophages versus WT macrophages reveals lower IjBa recovery and higher phosphorylation of JNK and p38a after 1 h of LPS stimulation. Moreover, Cot/tpl2 deficiency increases LPS-induced NO synthase 2 (NOS2) expression in macrophages. Inhibition of the PI3K pathway abolishes the differences in IjBa and NOS2 expression between Cot/tpl2 KO and WT macrophages following LPS administration. Furthermore, in zymosan-and polyI:C-stimulated macrophages, Cot/tpl2 mediates P-Ser473 Akt phosphorylation, increases IjBa levels and decreases NOS2 expression. In conclusion, these data reveal a novel role for the Cot/tpl2 pathway in mediating TLR activation of the Akt-mTOR-p70 S6k pathway, allowing Cot/tpl2 to fine-control the activation state of other signalling pathways.Key words: Akt . Cot/tpl2 . Macrophage . NO synthase 2 . p70 S6k . TLR See accompanying Commentary by Martinez Supporting Information available online IntroductionStimulation of TLRs by the different PAMPs triggers macrophage activation, starting a specific functional program that culminates in the production of inflammatory mediators. With the exception of TLR3, TLRs use MyD88 as a central intracellular adaptor, thereby activating multiple downstream intracellular pathways including IKK. TLR3 and TLR4 recruit the TRIF adaptor, which also activates IKK, but specifically activating TBK1 and the transcription factor IRF3 (reviewed in [1,2]). Translocation of IRF3 to the nucleus is necessary, although not sufficient, to induce IFN-b expression [3]. Most TLRs also activate the PI3K-Akt-mTOR-p70 S6k pathway, which is considered to be a negative regulator of TLR activation in macrophages and myeloid dendritic cells. Inhibition of this PI3K-Akt-mTOR-p70 S6k pathway in TLR-activated cells augments NO synthase 2 (NOS2) expression [4][5][6][7][8].Adequate TLR4 stimulation induces the formation of a TLR receptor complex that recruits proteins such as MyD88 and p85 PI3 K [9]. PI3K subsequently activates the Akt-mTOR-p70 S6k pathway. Moreover, TLR-bound MyD88 recruits IRAK4 and IRAK1. The phosphorylation of IRAK1 by IRAK4 facilitates TRAF6 [1,10]). Activated IKK-b phosphorylates p105 NF-kB at multiple residues [11][12][13], which targets the rapid degradation of p105 NF-kB to p50 NF-kB [11][12][13][14]. In resting cells, Cot/tpl-2 forms a stable and inactive complex with p105 NF-kB and ABIN2 (A20-binding inhibitor of NF-kB2), among other proteins, protecting Cot/tpl-2 from degradation. The partial proteolysis of p105 NFkB to p50 NF-kB releases Cot/tpl-2 from the complex [15][16][17][18][19][20]. Dissociated and adequately phosphorylated Cot/tpl2 [21][22][23][24] fully...

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Section: Resultssupporting

confidence: 92%

Section: Increased P38a and Jnk Phosphorylation And Impaired Ijba Recsupporting

confidence: 90%

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confidence: 97%

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Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

et al. 2011

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“…Furthermore, LPS stimulation activates the MEK kinase activity of TPL-2 [33,34]. TPL-2 is also required for TLR2, TLR9 and TNF activation of ERK in macrophages [35][36][37] and CD40 activation of ERK in B cells [35]. In other cell types, the function of TPL-2 may not be restricted to the regulation of the ERK MAP kinase pathway.…”

Section: S125mentioning

confidence: 99%

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Gantke¹,

Sriskantharajah²,

Ley³

2010

Cell Res

135

158

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The IκB kinase (IKK) complex plays a well-documented role in innate and adaptive immunity. This function has been widely attributed to its role as the central activator of the NF-κB family of transcription factors. However, another important consequence of IKK activation is the regulation of TPL-2, a MEK kinase that is required for activation of ERK-1/2 MAP kinases in myeloid cells following Toll-like receptor and TNF receptor stimulation. In unstimulated cells, TPL-2 is stoichiometrically complexed with the NF-κB inhibitory protein NF-κB1 p105, which blocks TPL-2 access to its substrate MEK, and the ubiquitin-binding protein ABIN-2 (A20-binding inhibitor of NF-κB 2), both of which are required to maintain TPL-2 protein stability. Following agonist stimulation, the IKK complex phosphorylates p105, triggering its K48-linked ubiquitination and degradation by the proteasome. This releases TPL-2 from p105-mediated inhibition, facilitating activation of MEK, in addition to modulating NF-κB activation by liberating associated Rel subunits for translocation into the nucleus. IKK-induced proteolysis of p105, therefore, can directly regulate both NF-κB and ERK MAP kinase activation via NF-κB1 p105. TPL-2 is critical for production of the proinflammatory cytokine TNF during inflammatory responses. Consequently, there has been considerable interest in the pharmaceutical industry to develop selective TPL-2 inhibitors as drugs for the treatment of TNF-dependent inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review summarizes our current understanding of the regulation of TPL-2 signaling function, and also the complex positive and negative roles of TPL-2 in immune and inflammatory responses.

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“…The TPL-2 MAPK signaling pathway gives rise to a complex network of cytokine regulation. While it is crucial for promoting the processing of the secreted form of the proinflammatory cytokine TNF-a [28], recent work has shown that it induces the anti-inflammatory cytokine IL-10 and negatively controls the proinflammatory cytokines IL-12 and IFN-b in macrophages and myeloid DC [29].MAPK3 has also been reported to phosphorylate and activate CdGAP, which is a negative regulator of the Rho GTPase Cdc42 [30]. This GTPase is an important regulator of actin dynamics.…”

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confidence: 99%

MAPK3 deficiency drives autoimmunity via DC arming

et al. 2010

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DC are professional APC that instruct T cells during the inflammatory course of EAE. We have previously shown that MAPK3 (Erk1) is important for the induction of T-cell anergy. Our goal was to determine the influence of MAPK3 on the capacity of DC to arm T-cell responses in autoimmunity. We report that DC from Mapk3 À/À mice have a significantly higher membrane expression of CD86 and MHC-II and -when loaded with the myelin oligodendrocyte glycoprotein -show a superior capacity to prime naïve T cells towards an inflammatory phenotype than Mapk3 1/1 DC. Nonetheless and as previously described, Mapk3 À/À mice were only slightly but not significantly more susceptible to myelin oligodendrocyte glycoprotein-induced EAE than WT littermate mice. However, Mapk3 1/1 mice engrafted with Mapk3 À/À BM (KO-WT) developed a severe form of EAE, in direct contrast to WT-KO mice, which were even less sick than control WT-WT mice. An infiltration of DC and accumulation of Th17 cells was also observed in the CNS of KO-WT mice. Therefore, triggering of MAPK3 in the periphery might be a therapeutic option for the treatment of neuroinflammation since absence of this kinase in the immune system leads to severe EAE.Key words: DC . EAE . MAPK3 . T-cell priming IntroductionIn order for living organisms to build up an immune response against dangerous entities it is fundamental that DC continuously patrol the periphery and sample their environment for danger signals [1]. Their distinct capacity to mobilize swiftly to lymphoid organs and alternate between antigen uptake and presentation makes DC decision-makers for inducing antigen-specific T-cell responses [2]. Previously we showed that the activation of MAPK3 or Erk1 but not its isoform MAPK1 (Erk2) accompanies, and is necessary for, the induction of T-cell anergy [3]. Since their identification [4], MAPK3 and its isoforms have been commonly ascribed analogous downstream functions due to their Ã These authors contributed equally to this work. 1486striking similarities. However, it is becoming increasingly clear that these isoforms -particularly MAPK3 and MAPK1 -have explicitly different functions. While MAPK1 has a more pronounced role in cell proliferation and developmental processes [5][6][7], MAPK3 does not seem to be required during development and its deficiency may be compensated for by MAPK1. In fact while Mapk À/À mice are lethal, Mapk3 À/À mice are viable and develop normally [8]. However, when challenged with CNS antigen Mapk3 À/À mice are more susceptible to undergo EAE [9,10]. So far, a deficiency of MAPK3 in the CNS has been associated with facilitated learning and long-term memory [11]. In the immune system, MAPK3 has been reported to play a key role in positive selection during T-cell development [8,12] and we have previously shown MAPK3 activation to be necessary for the induction of T-cell anergy [3].In this study we report that MAPK3 acts as a negative regulator of DC that controls their strength to prime T cells towards an inflammatory phenotype. Mapk3 À/À DC expressed ...

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TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cells

Cited by 150 publications

References 43 publications

Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

MAPK3 deficiency drives autoimmunity via DC arming

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