Protein kinase Cδ binds TIRAP/Mal to participate in TLR signaling

Kubo-Murai, Miho; Hazeki, Kaoru; Sukenobu, Naoe; Yoshikawa, K; Nigorikawa, Kiyomi; Inoue, Kazumi; Yamamoto, Toshiyoshi; Matsumoto, Misako; Seya, Tsukasa; Inoue, Norimitsu; Hazeki, Osamu

doi:10.1016/j.molimm.2006.11.005

Cited by 46 publications

(36 citation statements)

References 44 publications

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“…Several DAG-activated enzymes are known to be required for full downstream responses during LPS activation. For example, enzymes from the protein kinase C (PKC) family, such as PKCε and PKCd, can associate with different adaptor proteins that are recruited to TLR4 (32,33). Activation of PKCs requires phosphorylation and enhanced levels of DAG, and the action of these kinases affects TLR4 downstream pathways such as MAPK activation, which ensures full production of inflammatory factors (34).…”

Section: Discussionmentioning

confidence: 99%

Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

Meana

Peña

Lordén

et al. 2014

The Journal of Immunology

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Lipin-1 is a Mg2+-dependent phosphatidic acid phosphatase involved in the de novo synthesis of phospholipids and triglycerides. Using macrophages from lipin-1–deficient animals and human macrophages deficient in the enzyme, we show in this work that this phosphatase acts as a proinflammatory mediator during TLR signaling and during the development of in vivo inflammatory processes. After TLR4 stimulation lipin-1–deficient macrophages showed a decreased production of diacylglycerol and activation of MAPKs and AP-1. Consequently, the generation of proinflammatory cytokines like IL-6, IL-12, IL-23, or enzymes like inducible NO synthase and cyclooxygenase 2, was reduced. In addition, animals lacking lipin-1 had a faster recovery from endotoxin administration concomitant with a reduced production of harmful molecules in spleen and liver. These findings demonstrate an unanticipated role for lipin-1 as a mediator of macrophage proinflammatory activation and support a critical link between lipid biosynthesis and systemic inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

Meana

Peña

Lordén

et al. 2014

The Journal of Immunology

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“…Although previously published suppression of Mal phosphorylation by a Btk inhibitor LFM-A13 (55) and the interactions studies shown here suggest Btk as the key kinase responsible for tyrosine phosphorylation of Mal, we cannot rule out the involvement of other kinases. Interestingly, protein kinase C␦ (PKC␦) was also reported to bind Mal within its TIR domain, and PKC␦ depletion from RAW cells suppressed TLR2-and TLR4-induced signaling (62). Thus, the involvement of a multikinase complex (e.g.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance

Piao

Song

Chen

et al. 2008

Journal of Biological Chemistry

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“…MyD88 may activate, via several signaling molecules, the TGF-␤-activated kinase 1 (TAK1), which in turn activates among other things signaling pathways leading to the activation of p42/44 and JNK (43). PKC␦ has been shown recently to bind to a TLR signaling complex, namely TIRAP/Mal, and thus participate in TLR signaling (44). In addition, Kang et al showed a role of the phosphatase calcineurin in regulating TLR-activated pathways (30).…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor-4 Modulates Survival by Induction of Left Ventricular Remodeling after Myocardial Infarction in Mice

Riad

Jäger

Sobirey

et al. 2008

The Journal of Immunology

114

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Left ventricular (LV) remodeling is known to contribute to morbidity and mortality after myocardial infarction (MI). Because LV remodeling is strongly associated with an inflammatory response, we investigated whether or not TLR-4 influences LV remodeling and survival in a mice model of MI. Six days after MI induction, TLR4 knockout (KO)-MI mice showed improved LV function 32 and reduced LV remodeling as indexed by reduced levels of atrial natriuretic factor and total collagen as well as by a reduced heart weight to body weight ratio when compared with WT-MI mice. This was associated with a reduction of protein levels of the intracellular TLR4 adapter protein MyD88 and enhanced protein expression of the anti-hypertrophic JNK in KO-MI mice when compared with wild-type (WT)-MI mice. In contrast, protein activation of the pro-hypertrophic kinases protein kinase Cδ and p42/44 were not regulated in KO-MI mice when compared with WT-MI mice. Improved LV function, reduced cardiac remodeling, and suppressed intracellular TLR4 signaling in KO-MI mice were associated with significantly improved survival compared with WT-MI mice (62 vs 23%; p < 0.0001). TLR4 deficiency led to improved survival after MI mediated by attenuated left ventricular remodeling.

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Protein kinase Cδ binds TIRAP/Mal to participate in TLR signaling

Cited by 46 publications

References 44 publications

Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance

Toll-Like Receptor-4 Modulates Survival by Induction of Left Ventricular Remodeling after Myocardial Infarction in Mice

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