The Kinase Akt1 Controls Macrophage Response to Lipopolysaccharide by Regulating MicroRNAs

Androulidaki, Ariadne; Iliopoulos, Dimitrios; Arranz, Alicia; Doxaki, Christina; Schworer, Stephen; Zacharioudaki, Vassiliki; Margioris, Andrew N.; Tsichlis, Philip N.; Tsatsanis, Christos

doi:10.1016/j.immuni.2009.06.024

Cited by 534 publications

(592 citation statements)

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“…Furthermore, this novel attribute of Cot/tpl2 in the activation of Akt and p70 S6k is a selective and specific event, since Cot/tpl2 has no effect on the Ser473 Akt phosphorylation or on Thr389 p70 S6k phosphorylation in IL-10-stimulated BMDMs, which utilize a receptor that activates distinct intracellular pathways that the TLR/IL1 receptor super-family [41]. The PI3K-Akt-mTOR-p70 S6k pathway has an established role in restricting pro-inflammatory and promoting anti-inflammatory responses in TLR-stimulated macrophages [7,8,42]. The PI3K pathway represses MyD88-dependent activated pathways, increasing the recovery of IkBa expression and downmodulating the phosphorylation state of p38a, JNK and Erk1/2 in TLR-activated macrophages [4][5][6].…”

Section: Discussionmentioning

confidence: 99%

“…The PI3K-Akt-mTOR-p70 S6k pathway has an established role in restricting pro-inflammatory and promoting anti-inflammatory responses in TLR-stimulated macrophages [7,8,42]. The PI3K pathway represses MyD88-dependent activated pathways, increasing the recovery of IkBa expression and downmodulating the phosphorylation state of p38a, JNK and Erk1/2 in TLR-activated macrophages [4][5][6].…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…For the most part, primary miRNA transcription is dependent on the NF-kB transcription factor. 64,65 Additionally, TLR signals can negatively regulate miRNAs, including miR125b, let-7i and miR-98, [66][67][68] in certain cell types. Little is known about how TLR signals decrease miRNA expression, which most likely occurs through transcriptional repression or post-transcriptional destabilization of miRNA.…”

Section: Introductionmentioning

confidence: 99%

“…In mouse macrophages, let-7e is one of the TLR signaling-induced miRNAs. 68 After LPS stimulation, increased let-7e downregulates the surface TLR4 expression to avoid excessive inflammation and tissue damage. Suppression of let-7e action with an antisense miRNA probe leads to increased TLR4 expression and cytokine production after LPS challenge.…”

Section: Introductionmentioning

confidence: 99%

“…Suppression of let-7e action with an antisense miRNA probe leads to increased TLR4 expression and cytokine production after LPS challenge. 68 However, in epithelial cells, TLR4 mRNA is regulated by let-7i, which is decreased after TLR stimulation. Downregulation of let-7i increases the surface TLR4 level and the inflammatory response in these epithelial cells, 73 which may be due to the need of epithelial cells to enhance inflammation during infection, as they lack the professional capacity to recognize pathogens and express low amounts of TLR4 in a quiescent state.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNAs in the regulation of TLR and RIG-I pathways

2012

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The innate immune system recognizes invading pathogens through germline-encoded pattern recognition receptors (PRRs), which elicit innate antimicrobial and inflammatory responses and initiate adaptive immunity to control or eliminate infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) are the key innate immune PRRs and are tightly regulated by elaborate mechanisms to ensure a beneficial outcome in response to foreign invaders. Although much of the focus in the literature has been on the study of protein regulators of inflammation, microRNAs (miRNAs) have emerged as important controllers of certain features of the inflammatory process. Several miRNAs are induced by TLR and RIG-I activation in myeloid cells and act as feedback regulators of TLR and RIG-I signaling. In this review, we comprehensively discuss the recent understanding of how miRNA networks respond to TLR and RIG-I signaling and their role in the initiation and termination of inflammatory responses. Increasing evidence also indicates that both virus-encoded miRNAs and cellular miRNAs have important functions in viral replication and host anti-viral immunity.

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Leukocyte Reprogramming

Cavaillon

2017

Inflammation - From Molecular and Cellular Mechanisms to the Clinic

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The Kinase Akt1 Controls Macrophage Response to Lipopolysaccharide by Regulating MicroRNAs

Cited by 534 publications

References 50 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

MicroRNAs in the regulation of TLR and RIG-I pathways

Leukocyte Reprogramming

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