The phosphatidylinositol 3-kinase/Akt pathway negatively regulates Nod2-mediated NF-κB pathway

Ling Zhao, Joo Y. Lee, Daniel H. Hwang

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Nucleotide-binding oligomerization domain containing proteins (Nods) are intracellular pattern recognition receptors (PRRs) that recognize conserved moieties of bacterial peptidoglycan and activate downstream signaling pathways, including NF-κB pathway. Here, we show that Nod2 agonist muramyldipeptide (MDP) induces Akt phosphorylation in time and dose-dependent manner. The pharmacological inhibitor of phosphatidylinositol 3-kinase (PI3K) (wortmannin) and dominant-negative forms of p85 (the regulatory subunit of PI3K) or Akt enhance, while constitutive active forms of p110 (the catalytic subunit of PI3K) or Akt inhibit, NF-κB activation and the target gene interleukin (IL)-8 induced by MDP. In addition, the pharmacological inhibitors of PI3K (wortmannin and LY294002) enhance phosphorylation of NF-κB p65 on Ser529 and Ser536 residues, which result in enhanced p65 transactivation activity. Furthermore, we show that the inhibition of PI3K by the pharmacological inhibitors prevent the inactivation of glycogen synthase kinase (GSK)-3β, suggesting that the negative regulation of PI3K/Akt on MDP-induced NF-κB activation is at least in part mediated through inactivation of GSK-3β. Taken together, our results demonstrate that PI3K/Akt pathway is activated by Nod2 agonist MDP and negatively regulates NF-κB pathway downstream of Nod2 activation. Our results suggest that PI3K/Akt pathway may involve in the resolution of inflammatory responses induced by Nod2 activation.

Original languageEnglish (US)
Pages (from-to)1515-1525
Number of pages11
JournalBiochemical Pharmacology
Volume75
Issue number7
DOIs
StatePublished - Apr 1 2008
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Chemical activation
Glycogen Synthase Kinase 3
Phosphorylation
Pharmacology
Transcriptional Activation
Pattern Recognition Receptors
Oligomerization
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Peptidoglycan
Interleukin-8
Catalytic Domain
Nucleotides
Genes

Keywords

  • GSK-3β
  • Inflammation
  • NF-κB
  • Nod2
  • PI3K
  • Resolution

ASJC Scopus subject areas

  • Pharmacology

Cite this

The phosphatidylinositol 3-kinase/Akt pathway negatively regulates Nod2-mediated NF-κB pathway. / Zhao, Ling; Lee, Joo Y.; Hwang, Daniel H.

In: Biochemical Pharmacology, Vol. 75, No. 7, 01.04.2008, p. 1515-1525.

Research output: Contribution to journalArticle

Zhao, Ling ; Lee, Joo Y. ; Hwang, Daniel H. / The phosphatidylinositol 3-kinase/Akt pathway negatively regulates Nod2-mediated NF-κB pathway. In: Biochemical Pharmacology. 2008 ; Vol. 75, No. 7. pp. 1515-1525.
@article{0c317bb7d4f84ed3b2ae3be960a0d00b,
title = "The phosphatidylinositol 3-kinase/Akt pathway negatively regulates Nod2-mediated NF-κB pathway",
abstract = "Nucleotide-binding oligomerization domain containing proteins (Nods) are intracellular pattern recognition receptors (PRRs) that recognize conserved moieties of bacterial peptidoglycan and activate downstream signaling pathways, including NF-κB pathway. Here, we show that Nod2 agonist muramyldipeptide (MDP) induces Akt phosphorylation in time and dose-dependent manner. The pharmacological inhibitor of phosphatidylinositol 3-kinase (PI3K) (wortmannin) and dominant-negative forms of p85 (the regulatory subunit of PI3K) or Akt enhance, while constitutive active forms of p110 (the catalytic subunit of PI3K) or Akt inhibit, NF-κB activation and the target gene interleukin (IL)-8 induced by MDP. In addition, the pharmacological inhibitors of PI3K (wortmannin and LY294002) enhance phosphorylation of NF-κB p65 on Ser529 and Ser536 residues, which result in enhanced p65 transactivation activity. Furthermore, we show that the inhibition of PI3K by the pharmacological inhibitors prevent the inactivation of glycogen synthase kinase (GSK)-3β, suggesting that the negative regulation of PI3K/Akt on MDP-induced NF-κB activation is at least in part mediated through inactivation of GSK-3β. Taken together, our results demonstrate that PI3K/Akt pathway is activated by Nod2 agonist MDP and negatively regulates NF-κB pathway downstream of Nod2 activation. Our results suggest that PI3K/Akt pathway may involve in the resolution of inflammatory responses induced by Nod2 activation.",
keywords = "GSK-3β, Inflammation, NF-κB, Nod2, PI3K, Resolution",
author = "Ling Zhao and Lee, {Joo Y.} and Hwang, {Daniel H.}",
year = "2008",
month = "4",
day = "1",
doi = "10.1016/j.bcp.2007.12.014",
language = "English (US)",
volume = "75",
pages = "1515--1525",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "7",

}

TY - JOUR

T1 - The phosphatidylinositol 3-kinase/Akt pathway negatively regulates Nod2-mediated NF-κB pathway

AU - Zhao, Ling

AU - Lee, Joo Y.

AU - Hwang, Daniel H.

PY - 2008/4/1

Y1 - 2008/4/1

N2 - Nucleotide-binding oligomerization domain containing proteins (Nods) are intracellular pattern recognition receptors (PRRs) that recognize conserved moieties of bacterial peptidoglycan and activate downstream signaling pathways, including NF-κB pathway. Here, we show that Nod2 agonist muramyldipeptide (MDP) induces Akt phosphorylation in time and dose-dependent manner. The pharmacological inhibitor of phosphatidylinositol 3-kinase (PI3K) (wortmannin) and dominant-negative forms of p85 (the regulatory subunit of PI3K) or Akt enhance, while constitutive active forms of p110 (the catalytic subunit of PI3K) or Akt inhibit, NF-κB activation and the target gene interleukin (IL)-8 induced by MDP. In addition, the pharmacological inhibitors of PI3K (wortmannin and LY294002) enhance phosphorylation of NF-κB p65 on Ser529 and Ser536 residues, which result in enhanced p65 transactivation activity. Furthermore, we show that the inhibition of PI3K by the pharmacological inhibitors prevent the inactivation of glycogen synthase kinase (GSK)-3β, suggesting that the negative regulation of PI3K/Akt on MDP-induced NF-κB activation is at least in part mediated through inactivation of GSK-3β. Taken together, our results demonstrate that PI3K/Akt pathway is activated by Nod2 agonist MDP and negatively regulates NF-κB pathway downstream of Nod2 activation. Our results suggest that PI3K/Akt pathway may involve in the resolution of inflammatory responses induced by Nod2 activation.

AB - Nucleotide-binding oligomerization domain containing proteins (Nods) are intracellular pattern recognition receptors (PRRs) that recognize conserved moieties of bacterial peptidoglycan and activate downstream signaling pathways, including NF-κB pathway. Here, we show that Nod2 agonist muramyldipeptide (MDP) induces Akt phosphorylation in time and dose-dependent manner. The pharmacological inhibitor of phosphatidylinositol 3-kinase (PI3K) (wortmannin) and dominant-negative forms of p85 (the regulatory subunit of PI3K) or Akt enhance, while constitutive active forms of p110 (the catalytic subunit of PI3K) or Akt inhibit, NF-κB activation and the target gene interleukin (IL)-8 induced by MDP. In addition, the pharmacological inhibitors of PI3K (wortmannin and LY294002) enhance phosphorylation of NF-κB p65 on Ser529 and Ser536 residues, which result in enhanced p65 transactivation activity. Furthermore, we show that the inhibition of PI3K by the pharmacological inhibitors prevent the inactivation of glycogen synthase kinase (GSK)-3β, suggesting that the negative regulation of PI3K/Akt on MDP-induced NF-κB activation is at least in part mediated through inactivation of GSK-3β. Taken together, our results demonstrate that PI3K/Akt pathway is activated by Nod2 agonist MDP and negatively regulates NF-κB pathway downstream of Nod2 activation. Our results suggest that PI3K/Akt pathway may involve in the resolution of inflammatory responses induced by Nod2 activation.

KW - GSK-3β

KW - Inflammation

KW - NF-κB

KW - Nod2

KW - PI3K

KW - Resolution

UR - http://www.scopus.com/inward/record.url?scp=40849118049&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=40849118049&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2007.12.014

DO - 10.1016/j.bcp.2007.12.014

M3 - Article

C2 - 18243161

AN - SCOPUS:40849118049

VL - 75

SP - 1515

EP - 1525

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 7

ER -