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The Phosphatidylinositol 3‐Kinase/Akt Pathway Negatively Regulates Nod2‐Mediated NF‐kappaB Pathway
Author(s) -
Zhao Ling,
Lee Joo Y.,
Hwang Daniel H.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.320.3
Subject(s) - wortmannin , pi3k/akt/mtor pathway , protein kinase b , transactivation , phosphorylation , microbiology and biotechnology , chemistry , ly294002 , signal transduction , nod2 , kinase , biology , biochemistry , receptor , gene expression , gene , innate immune system
Nucleotide‐binding oligomerization domain containing proteins (Nods) are intracellular pattern recognition receptors that recognize conserved moieties of bacterial peptidoglycan and activate downstream signaling pathways, including NF‐kappaB. Here, we show that Nod2 agonist MDP induces Akt phosphorylation in time and dose dependent manner. Pharmacological inhibitors of PI3K (LY294002 and wortmannin) and dominant negative form of p85 (the regulatory subunit of PI3K) or Akt enhance, while constitutive active form of p110 (the catalytic subunit of PI3K) or Akt inhibit, NF‐kappaB activation and the target gene IL‐8 induced by MDP. In addition, both LY 294002 and wortmannin enhance phosphorylation of NF‐kappaB p65 on Ser 529 and Ser 536 residues resulting in enhanced p65 transactivation activity. Furthermore, we show that the negative regulation of PI3K/Akt on MDP‐induced NF‐kappaB is in part mediated through inactivating glycogen synthase kinase (GSK)‐3Beta. Together, our results demonstrate that PI3K/Akt pathway is activated by MDP and negatively regulates NF‐kappaB pathway downstream of Nod2 activation, suggesting that PI3K/Akt pathway may involve in the resolution of inflammatory responses induced by Nod2 activation. This work was supported by grants DK064007, DK41868, and CA75613 from the National Institutes of Health.