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

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

研究成果: 雜誌貢獻文章

37 引文 (Scopus)

摘要

Calcium/calmodulin-dependent protein kinase kinase (CaMKK) and Akt are two multifunctional kinases involved in many cellular responses. Although Akt and Ca2+ signals have been implicated in NF-κB activation in response to certain stimuli, these results are still controversial, and the mechanism(s) involved remains unknown. In this study, we show the roles that CaMKK and Akt play in regulating interleukin-1β (IL-1β)-induced NF-κB signaling. In human embryonic kidney 293 cells, IL-1β induces IκB kinase β (IKKβ) activation, IκBα degradation, NF-κB transactivation, and weak Akt activation. A CaMKK inhibitor (KN-93) and phosphatidylinositol 3-kinase inhibitors (wortmannin and LY294002) do not inhibit IL-1β-induced NF-κB activation. However, IL-1β-induced NF-κB activity is attenuated by increased intracellular calcium in response to ionomycin, UTP, or thapsigargin or by overexpression of CaMKKc and/or Akt. Ionomycin and CaMKKc overexpression increases Akt phosphorylation on Thr308 and enzyme activity. Under these conditions or upon overexpression of wild type Akt, IL-1β-induced IKKβ activity is diminished. Furthermore, a dominant negative mutant of Akt abolishes IKKβ inhibition by CaMKKc and ionomycin, suggesting that Akt acts as a mediator of CaMKK signaling to inhibit IL-1β-induced IKK activity at an upstream target site. We have also identified a novel interaction between CaMKK-stimulated Akt and interleukin-1 receptor-associated kinase I (IRAK1), which plays a key role in IL-1β-induced NF-κB activation. CaMKKc and Akt overexpression decreases IRAK1-mediated NF-κB activity and its association with MyD88 in response to IL-1β stimulation. Furthermore, CaMKKc and Akt over-expression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-κB activation. Taken together, these results indicate a novel regulatory mechanism for IL-1β signaling and suggest that CaMKK-dependent Akt activation inhibits IL-1β-induced NF-κB activation through interference with the coupling of IRAK1 to MyD88.
原文英語
頁(從 - 到)24169-24179
頁數11
期刊Journal of Biological Chemistry
277
發行號27
DOIs
出版狀態已發佈 - 七月 5 2002
對外發佈Yes

指紋

Calcium-Calmodulin-Dependent Protein Kinase Kinase
Interleukin-1 Receptor-Associated Kinases
Phosphorylation
Interleukin-1
Chemical activation
Calcium-Calmodulin-Dependent Protein Kinases
Phosphotransferases
Ionomycin
Phosphatidylinositol 3-Kinase
Uridine Triphosphate
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Thapsigargin
Enzyme activity
Point Mutation
Transcriptional Activation

ASJC Scopus subject areas

  • Biochemistry

引用此文

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title = "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",
abstract = "Calcium/calmodulin-dependent protein kinase kinase (CaMKK) and Akt are two multifunctional kinases involved in many cellular responses. Although Akt and Ca2+ signals have been implicated in NF-κB activation in response to certain stimuli, these results are still controversial, and the mechanism(s) involved remains unknown. In this study, we show the roles that CaMKK and Akt play in regulating interleukin-1β (IL-1β)-induced NF-κB signaling. In human embryonic kidney 293 cells, IL-1β induces IκB kinase β (IKKβ) activation, IκBα degradation, NF-κB transactivation, and weak Akt activation. A CaMKK inhibitor (KN-93) and phosphatidylinositol 3-kinase inhibitors (wortmannin and LY294002) do not inhibit IL-1β-induced NF-κB activation. However, IL-1β-induced NF-κB activity is attenuated by increased intracellular calcium in response to ionomycin, UTP, or thapsigargin or by overexpression of CaMKKc and/or Akt. Ionomycin and CaMKKc overexpression increases Akt phosphorylation on Thr308 and enzyme activity. Under these conditions or upon overexpression of wild type Akt, IL-1β-induced IKKβ activity is diminished. Furthermore, a dominant negative mutant of Akt abolishes IKKβ inhibition by CaMKKc and ionomycin, suggesting that Akt acts as a mediator of CaMKK signaling to inhibit IL-1β-induced IKK activity at an upstream target site. We have also identified a novel interaction between CaMKK-stimulated Akt and interleukin-1 receptor-associated kinase I (IRAK1), which plays a key role in IL-1β-induced NF-κB activation. CaMKKc and Akt overexpression decreases IRAK1-mediated NF-κB activity and its association with MyD88 in response to IL-1β stimulation. Furthermore, CaMKKc and Akt over-expression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-κB activation. Taken together, these results indicate a novel regulatory mechanism for IL-1β signaling and suggest that CaMKK-dependent Akt activation inhibits IL-1β-induced NF-κB activation through interference with the coupling of IRAK1 to MyD88.",
author = "Chen, {Bing Chang} and Wu, {Wen Tung} and Ho, {Feng Ming} and Lin, {Wan Wan}",
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T1 - 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

AU - Chen, Bing Chang

AU - Wu, Wen Tung

AU - Ho, Feng Ming

AU - Lin, Wan Wan

PY - 2002/7/5

Y1 - 2002/7/5

N2 - Calcium/calmodulin-dependent protein kinase kinase (CaMKK) and Akt are two multifunctional kinases involved in many cellular responses. Although Akt and Ca2+ signals have been implicated in NF-κB activation in response to certain stimuli, these results are still controversial, and the mechanism(s) involved remains unknown. In this study, we show the roles that CaMKK and Akt play in regulating interleukin-1β (IL-1β)-induced NF-κB signaling. In human embryonic kidney 293 cells, IL-1β induces IκB kinase β (IKKβ) activation, IκBα degradation, NF-κB transactivation, and weak Akt activation. A CaMKK inhibitor (KN-93) and phosphatidylinositol 3-kinase inhibitors (wortmannin and LY294002) do not inhibit IL-1β-induced NF-κB activation. However, IL-1β-induced NF-κB activity is attenuated by increased intracellular calcium in response to ionomycin, UTP, or thapsigargin or by overexpression of CaMKKc and/or Akt. Ionomycin and CaMKKc overexpression increases Akt phosphorylation on Thr308 and enzyme activity. Under these conditions or upon overexpression of wild type Akt, IL-1β-induced IKKβ activity is diminished. Furthermore, a dominant negative mutant of Akt abolishes IKKβ inhibition by CaMKKc and ionomycin, suggesting that Akt acts as a mediator of CaMKK signaling to inhibit IL-1β-induced IKK activity at an upstream target site. We have also identified a novel interaction between CaMKK-stimulated Akt and interleukin-1 receptor-associated kinase I (IRAK1), which plays a key role in IL-1β-induced NF-κB activation. CaMKKc and Akt overexpression decreases IRAK1-mediated NF-κB activity and its association with MyD88 in response to IL-1β stimulation. Furthermore, CaMKKc and Akt over-expression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-κB activation. Taken together, these results indicate a novel regulatory mechanism for IL-1β signaling and suggest that CaMKK-dependent Akt activation inhibits IL-1β-induced NF-κB activation through interference with the coupling of IRAK1 to MyD88.

AB - Calcium/calmodulin-dependent protein kinase kinase (CaMKK) and Akt are two multifunctional kinases involved in many cellular responses. Although Akt and Ca2+ signals have been implicated in NF-κB activation in response to certain stimuli, these results are still controversial, and the mechanism(s) involved remains unknown. In this study, we show the roles that CaMKK and Akt play in regulating interleukin-1β (IL-1β)-induced NF-κB signaling. In human embryonic kidney 293 cells, IL-1β induces IκB kinase β (IKKβ) activation, IκBα degradation, NF-κB transactivation, and weak Akt activation. A CaMKK inhibitor (KN-93) and phosphatidylinositol 3-kinase inhibitors (wortmannin and LY294002) do not inhibit IL-1β-induced NF-κB activation. However, IL-1β-induced NF-κB activity is attenuated by increased intracellular calcium in response to ionomycin, UTP, or thapsigargin or by overexpression of CaMKKc and/or Akt. Ionomycin and CaMKKc overexpression increases Akt phosphorylation on Thr308 and enzyme activity. Under these conditions or upon overexpression of wild type Akt, IL-1β-induced IKKβ activity is diminished. Furthermore, a dominant negative mutant of Akt abolishes IKKβ inhibition by CaMKKc and ionomycin, suggesting that Akt acts as a mediator of CaMKK signaling to inhibit IL-1β-induced IKK activity at an upstream target site. We have also identified a novel interaction between CaMKK-stimulated Akt and interleukin-1 receptor-associated kinase I (IRAK1), which plays a key role in IL-1β-induced NF-κB activation. CaMKKc and Akt overexpression decreases IRAK1-mediated NF-κB activity and its association with MyD88 in response to IL-1β stimulation. Furthermore, CaMKKc and Akt over-expression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-κB activation. Taken together, these results indicate a novel regulatory mechanism for IL-1β signaling and suggest that CaMKK-dependent Akt activation inhibits IL-1β-induced NF-κB activation through interference with the coupling of IRAK1 to MyD88.

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