Phosphatidylinositol 3-kinase interacts with the glucocorticoid receptor upon TLR2 activation.
Bottom Line: Mutations of two tyrosine residues in the GR, 598 and 663, to phenylalanine significantly reduced interaction with PI3K and the GC effects on TLR2-induced TNF-α expression.However, these mutations did not alter GR transcriptional activity nor affect cellular localization of the expressed mutant GR in COS-1 cells.Therefore, the PI3K-GR interaction may contribute to the effects of GC on the TLR2 pro-inflammatory signalling cascade, thus defining a novel signalling mechanism with a profound impact on innate immune responses.
Affiliation: Immunology Disciplinary Program, Biomedical Sciences Institute, School of Medicine, University of Chile, Santiago, Chile.Show MeSH
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Mentions: To determine the role of the PI3K pathway on TLR2-mediated pro-inflammatory cytokine production, we analysed the effect of PI3K on the expression of TNF-α upon TLR2 activation in the presence or absence of dexamethasone. Expression of TNF-α was studied in A549 cells expressing a dominant negative construct of the PI3K subunit p85 (Δ478–511) which lacks the p110-binding domain (p85-DN) stimulated with Pam3-Cys-Ser-Lys4 alone or in combination with dexamethasone. PI3K intervention with the p85-DN induced a significant increase in TNF-α intracellular expression that was greatly enhanced with 20 μg/ml of Pam3-Cys-Ser-Lys4. Dexamethasone addition did not increase TNF-α when PI3K was abrogated (Fig. 2A).
Affiliation: Immunology Disciplinary Program, Biomedical Sciences Institute, School of Medicine, University of Chile, Santiago, Chile.