Inhibition of Interleukin-1β-induced NF-κB Activation by Calcium/Calmodulin-dependent Protein Kinase Kinase Occurs through Akt Activation Associated with Interleukin-1 Receptor-associated Kinase Phosphorylation and Uncoupling of MyD88

Chen, Bing Chang; Wu, Wen Tung; Ho, Feng Ming; Lin, Wan-Wan

doi:10.1074/jbc.m106014200

Cited by 57 publications

(39 citation statements)

References 65 publications

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“…Posttranslational modifications such as phosphorylation by Akt or CaMK were previously proposed to prevent IRAK-1 autophosphorylation. 10 However, in the present study the apoE-induced suppression of IB phosphorylation and NF-B activation were both retained in the presence of Akt and CaMK inhibitors, thus excluding the involvement of both kinases in the inhibitory effects of apoE on IL-1␤ signaling. Hence, apoE seems to target IRAK-1 function by other mechanisms that may include functional modifications of either IRAK-1 or IRAK-4.…”

Section: Discussionmentioning

confidence: 51%

“…8,9 In addition, Akt and calcium/calmodulin-dependent protein kinase (CaMK) phosphorylate and inhibit IRAK-1. 10 As shown in Figure 5A, the inhibitory effects of apoE on NF-B and AP-1 activity as well as IB and JNK phosphorylation in response to IL-1␤ were attenuated in VSMCs pretreated with H89, the pharmacological inhibitor of PKA, and SQ22536, the inhibitor of adenylate cyclase, which is an upstream activator of PKA. By contrast, KN93, the CaMK inhibitor, and LY294002, the Akt inhibitor, failed to interfere with the inhibitory effects of apoE.…”

Section: Ldl Receptor-related Protein 1 and Protein Kinase A Are Invomentioning

confidence: 94%

“…Posttranslational modifications such as phosphorylation by Akt or CaMK were previously proposed to prevent IRAK-1 autophosphorylation. 10 However, in the present study the apoE-induced suppression of IB phosphorylation and NF-B activation were both retained in the presence of Akt and CaMK inhibitors, thus 33 P]orthophosphate-labeled VSMCs were stimulated for 10 minutes with IL-1␤ (10 ng/mL) in the presence of apoE or 8Br-cAMP. Phosphorylated IRAK-1 was analyzed by autoradiography or scintillation spectrometry.…”

mentioning

confidence: 99%

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Apolipoprotein E Interrupts Interleukin-1β Signaling in Vascular Smooth Muscle Cells

Kawamura¹,

Baitsch²,

Telgmann³

et al. 2007

ATVB

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Objectives-Apolipoprotein E (apoE) exerts antiatherogenic effects but precise mechanisms remain unclear. We here investigated the effect of apoE on intracellular signaling by interleukin-1␤ (IL-1␤), a proinflammatory cytokine present in atherosclerotic lesions. Methods and Results-IL-1␤-induced expression and activation of inducible nitric oxide synthase and cyclooxygenase-2 were inhibited by apoE in vascular smooth muscle cells (VSMCs). These inhibitory effects were linked to the suppression of both NF-B and activating protein-1 (AP-1) transactivation, suggesting that the interruption of IL-1␤ signaling occurs upstream of transcription factors. Studies in VSMCs overexpressing IL-1␤ signaling intermediates revealed that NF-B transactivation was inhibited by apoE in MyD88-and IRAK1-but not in TRAF6-transfected cells. Furthermore, apoE prevented IRAK1 phosphorylation and IRAK1-TRAF6 but not MyD88-IRAK1 complex formation. Inhibitory effects of apoE on IL-1␤ signaling were abolished after silencing LDL receptor-related protein-1 (LRP1) expression with siRNA. In addition, inhibitors of adenylyl cyclase and protein kinase A (PKA) restored IL-1␤ signaling in apoE-treated VSMCs, whereas apoE stimulated PKA activity. ApoE inhibited VSMC activation in response to IL-18 but not to tumor necrosis factor-␣ or polyinosinic:polycytidylic acid. A polipoprotein E (apoE) is a major protein component of plasma lipoproteins and plays an important role in preventing atherosclerosis. The antiatherogenic effects of apoE are usually attributed to its ability to promote cholesterol efflux from peripheral cells for reverse cholesterol transport and to facilitate hepatic clearance of very low density lipoprotein (VLDL) and chylomicron remnants. However, apoE protects against atherosclerosis even in experimental settings, in which its effects on plasma cholesterol are negligible. For instance, transgenic expression of apoE in arterial wall led to inhibition of atheroma formation without affecting plasma lipoprotein profile. 1,2 Conversely, acceleration of atherosclerosis was observed in apoE ϩ/ϩ animals after transplantation of bone marrow from apoE-deficient mouse. 3 These results suggest that apoE directly inhibits the development of atherosclerosis in a manner independent of its role in cholesterol transport. Conclusion-ApoEAtherosclerosis is commonly regarded as a chronic inflammatory disease. Inflammation mediators such as cytokines and chemokines were shown to significantly contribute to the formation of atherosclerotic lesions, whereas antiinflammatory factors play the opposite role. ApoE has been previously suggested to suppress the expression of adhesion molecules on endothelial surface and thereby to prevent monocyte recruitment into the arterial intima. 4 However, little information is available concerning the involvement of apoE in initiation and perpetuation of inflammation within the vascular wall. In the present study, we examined the influence of apoE on cellular effects of interleukin-1␤ (IL-1␤), a proinflammatory cytok...

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Section: Discussionmentioning

confidence: 51%

Section: Ldl Receptor-related Protein 1 and Protein Kinase A Are Invomentioning

confidence: 94%

“…Posttranslational modifications such as phosphorylation by Akt or CaMK were previously proposed to prevent IRAK-1 autophosphorylation. 10 However, in the present study the apoE-induced suppression of IB phosphorylation and NF-B activation were both retained in the presence of Akt and CaMK inhibitors, thus 33 P]orthophosphate-labeled VSMCs were stimulated for 10 minutes with IL-1␤ (10 ng/mL) in the presence of apoE or 8Br-cAMP. Phosphorylated IRAK-1 was analyzed by autoradiography or scintillation spectrometry.…”

mentioning

confidence: 99%

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Apolipoprotein E Interrupts Interleukin-1β Signaling in Vascular Smooth Muscle Cells

Kawamura¹,

Baitsch²,

Telgmann³

et al. 2007

ATVB

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“…CaMKKs fit the criteria of being inhibited by STO-609 and presumably the CaMcompetitive KN-compounds (9,29,50), although a direct effect on CaMKK by the latter remains to be confirmed by in vitro studies. Therefore, we propose the involvement of CaMKK(s) in the regulation of Thr 172 ␣-AMPK phosphorylation in mouse skeletal muscle.…”

Section: Discussionmentioning

confidence: 94%

Possible CaMKK-dependent regulation of AMPK phosphorylation and glucose uptake at the onset of mild tetanic skeletal muscle contraction

Jensen

Rose

Jørgensen

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

183

187

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Jensen TE, Rose AJ, Jørgensen SB, Brandt N, Schjerling P, Wojtaszewski JF, Richter EA. Possible CaMKK-dependent regulation of AMPK phosphorylation and glucose uptake at the onset of mild tetanic skeletal muscle contraction. Am J Physiol Endocrinol Metab 292: E1308 -E1317, 2007. First published January 9, 2007; doi:10.1152/ajpendo.00456.2006 /calmodulin (CaM) competitive inhibitor KN-93 has previously been used to evaluate 5Ј-AMP-activated protein kinase (AMPK)-independent Ca 2ϩ -signaling to contraction-stimulated glucose uptake in muscle during intense electrical stimulation ex vivo. With the use of low-intensity tetanic contraction of mouse soleus and extensor digitorum longus (EDL) muscles ex vivo, this study demonstrates that KN-93 can potently inhibit AMPK phosphorylation and activity after 2 min but not 10 min of contraction while strongly inhibiting contraction-stimulated 2-deoxyglucose uptake at both the 2-and 10-min time points. These data suggest inhibition of Ca 2ϩ /CaM-dependent signaling events upstream of AMPK, the most likely candidate being the novel AMPK kinase CaM-dependent protein kinase kinase (CaMKK). CaMKK protein expression was detected in mouse skeletal muscle. Similar to KN-93, the CaMKK inhibitor STO-609 strongly reduced AMPK phosphorylation and activity at 2 min and less potently at 10 min. Pretreatment with STO-609 inhibited contraction-stimulated glucose uptake at 2 min in soleus, but not EDL, and in both muscles after 10 min. Neither KN-93 nor STO-609 inhibited 5-aminoimidazole-4-carboxamide-1-␤-4-ribofuranoside-stimulated glucose uptake, AMPK phosphorylation, or recombinant LKB1 activity, suggestive of an LKB1-independent effect. Finally, neither KN-93 nor STO-609 had effects on the reductions in glucose uptake seen in mice overexpressing a kinase-dead AMPK construct, indicating that the effects of KN-93 and STO-609 on glucose uptake require inhibition of AMPK activity. We propose that CaMKKs act in mouse skeletal muscle regulating AMPK phosphorylation and glucose uptake at the onset of mild tetanic contraction and that an intensity-and/or time-dependent switch occurs in the relative importance of AMPKKs during contraction.

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“…Our high-confidence anti-apoptotic 'hits' also included Camkk2 and Jak2. Akt activation by calcium/ calmodulin-dependent protein kinase kinase 2 beta, inhibits IL-1β-induced NF-κB activation [39]; Camkk2 can thus act as an anti-apoptotic gene in beta cells. Janus kinase 2, which phosphorylates signal transducer and activator of transcription 3, increases suppressor of cytokine signalling 3 production, thereby protecting pancreatic islets from cytokine-induced apoptosis [40].…”

Section: Discussionmentioning

confidence: 99%

An siRNA screen identifies transmembrane 7 superfamily member 3 (TM7SF3), a seven transmembrane orphan receptor, as an inhibitor of cytokine-induced death of pancreatic beta cells

et al. 2011

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Aims/hypothesis Pro-inflammatory cytokines induce death of pancreatic beta cells, leading to the development of type 1 diabetes. We sought to identify novel players and the underlying mechanisms involved in this process. Methods A high-throughput screen of 3,850 mouse small interfering RNAs (siRNAs) was performed in cytokinetreated MIN6 beta cells. Cells were transfected with the different siRNAs and then treated with a combination of TNFα, IL-1β and IFNγ. Cellular apoptosis (caspase-3/7 activity), and changes in cellular reducing power and cell morphology were monitored. The resulting data were analysed and the corresponding z scores calculated. Results Several gene families were identified as promoting cytokine-induced beta cell apoptosis, the most prominent being those encoding ubiquitin ligases and serine/threonine kinases. Conversely, deubiquitinating enzymes appeared to reduce apoptosis, while protein phosphatases were mainly associated with lowering cellular reducing power. The screen suggested with high confidence the involvement of several novel genes in cytokine-induced beta cell death, including Camkk2, Epn3, Foxp3 and Tm7sf3, which encodes an orphan seven transmembrane receptor. siRNAs to Tm7sf3 promoted cytokine-induced death of MIN6 cells and human pancreatic islets, and abrogated insulin secretion in these cells. These findings implicate transmembrane 7 superfamily member 3 as a potential new player in the inhibition of cytokine-induced death and in the promotion of insulin secretion from pancreatic beta cells. Conclusions/interpretation The signalling pathways and novel genes that we identified in this screen and that mediate beta cell death offer new possible targets for therapeutic intervention in diabetes and its adverse complications.

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Inhibition of Interleukin-1β-induced NF-κB Activation by Calcium/Calmodulin-dependent Protein Kinase Kinase Occurs through Akt Activation Associated with Interleukin-1 Receptor-associated Kinase Phosphorylation and Uncoupling of MyD88

Cited by 57 publications

References 65 publications

Apolipoprotein E Interrupts Interleukin-1β Signaling in Vascular Smooth Muscle Cells

Apolipoprotein E Interrupts Interleukin-1β Signaling in Vascular Smooth Muscle Cells

Possible CaMKK-dependent regulation of AMPK phosphorylation and glucose uptake at the onset of mild tetanic skeletal muscle contraction

An siRNA screen identifies transmembrane 7 superfamily member 3 (TM7SF3), a seven transmembrane orphan receptor, as an inhibitor of cytokine-induced death of pancreatic beta cells

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