A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA–induced IL-12 production and Th cell differentiation

Sugimoto, Kenji; Ohata, Mutsuhiro; Miyoshi, Jun; Ishizaki, Hiroki; Tsuboi, Nobuyuki; Matsubara, Akio; Yoshikai, Yasunobu; Takamoto, Masaya; Sugane, Kazuo; Matsuo, Seiichi; Shimada, Yasuhiro; Matsuguchi, Tetsuya

doi:10.1172/jci200420014

Cited by 47 publications

(82 citation statements)

References 40 publications

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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: Knockdown Of Cot/tpl-2 Enhances Lps-induced Nos2 Expression supporting

confidence: 92%

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: Knockdown Of Cot/tpl-2 Enhances Lps-induced Nos2 Expression supporting

confidence: 92%

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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“…In contrast to the above-mentioned studies suggesting a requirement for TPL-2 in Th1 differentiation, an independently generated Tpl2 −/− mouse strain has been reported to mount a Th1-skewed immune response following Leishmania major infection [79], possibly due to the increased production of IL-12 by TPL-2-deficient innate immune cells. These conflicting results may be explained by differences in how the two Tpl2 −/− mouse strains were generated, genetic background differences of the mice or by differential responses elicited by the two pathogens npg used in the studies.…”

Section: Regulation Of Immune and Inflammatory Responses By Tpl-2mentioning

confidence: 67%

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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“…It has been proven that Tpl2 is indispensable for LPS-induced ERK1/2 activation 4 . However, Tpl2 deficiency completely blocked LPS-induced ERK1/2 activation but did not affect CpG-induced ERK1/2 activation in mouse peritoneal macrophages 28 . These results indicate that TLR4 and TLR9 use different signal transduction mediators to activate downstream MAPKs.…”

Section: Discussionmentioning

confidence: 83%

Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages

Wen

Cheng

et al. 2015

Nat Commun

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A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA–induced IL-12 production and Th cell differentiation

Cited by 47 publications

References 40 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

Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages

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