The 15-Deoxy-δ12,14-Prostaglandin J2 Inhibits the Inflammatory Response in Primary Rat Astrocytes via Down-Regulating Multiple Steps in Phosphatidylinositol 3-Kinase-Akt-NF-κB-p300 Pathway Independent of Peroxisome Proliferator-Activated Receptor γ

• DOI: 10.4049/jimmunol.173.8.5196
• Publication Date: 2014-04-21T02:29:16Z
• Authors: Shailendra Giri; Ramandeep Rattan; Avtar K. Singh; Inderjit Singh
• Keywords: Lipopolysaccharides; 0303 health sciences; Prostaglandin D2; Anti-Inflammatory Agents; NF-kappa B; Down-Regulation; Nitric Oxide Synthase Type II; Nuclear Proteins; Protein Serine-Threonine Kinases; Nitric Oxide; I-kappa B Kinase; Interferon-gamma; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Gene Expression Regulation; Astrocytes; Proto-Oncogene Proteins; Animals; Nitric Oxide Synthase; E1A-Associated p300 Protein; Cells, Cultured; Phosphoinositide-3 Kinase Inhibitors

Abstract Ligands for peroxisome proliferator-activated receptor γ (PPARγ), such as 15-deoxy-12,14-PGJ2 (15d-PGJ2), have been proposed as a new class of anti-inflammatory compounds because 15d-PGJ2 was able to inhibit the induction of inflammatory response genes such as inducible NO synthase (iNOS) and TNF (TNF-α) in a PPAR-dependent manner in various cell types. In primary astrocytes, the anti-inflammatory effects (inhibition of TNF-α, IL-1β, IL-6, and iNOS gene expression) of 15d-PGJ2 are observed to be independent of PPARγ. Overexpression (wild-type and dominant-negative forms) of PPARγ and its antagonist (GW9662) did not alter the 15d-PGJ2-induced inhibition of LPS/IFN-γ-mediated iNOS and NF-κB activation. The 15d-PGJ2 inhibited the inflammatory response by inhibiting IκB kinase activity, which leads to the inhibition of degradation of IκB and nuclear translocation of p65, thereby regulating the NF-κB pathway. Moreover, 15d-PGJ2 also inhibited the LPS/IFN-γ-induced PI3K-Akt pathway. The 15d-PGJ2 inhibited the recruitment of p300 by NF-κB (p65) and down-regulated the p300-mediated induction of iNOS and NF-κB luciferase reporter activity. Coexpression of constitutive active Akt and PI3K (p110) reversed the 15d-PGJ2-mediated inhibition of p300-induced iNOS and NF-κB luciferase activity. This study demonstrates that 15d-PGJ2 suppresses inflammatory response by inhibiting NF-κB signaling at multiple steps as well as by inhibiting the PI3K/Akt pathway independent of PPARγ in primary astrocytes.