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The 15-Deoxy-12,14-Prostaglandin J₂ Inhibits the Inflammatory Response in Primary Rat Astrocytes via Down-Regulating Multiple Steps in Phosphatidylinositol 3-Kinase-Akt-NF-B-p300 Pathway Independent of Peroxisome Proliferator-Activated Receptor ¹

Shailendra Giri^*, Ramandeep Rattan^*, Avtar K. Singh^, and Inderjit Singh^2,*

Departments of ^* Pediatrics and Pathology and Laboratory Medicine, Medical University of South Carolina, and Department of Pathology and Laboratory Medicine, Ralph Johnson Veterans Affairs Medical Center, Charleston, SC 29425

Ligands for peroxisome proliferator-activated receptor (PPAR), 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-) in a PPAR-dependent manner in various cell types. In primary astrocytes, the anti-inflammatory effects (inhibition of TNF-, IL-1, IL-6, and iNOS gene expression) of 15d-PGJ₂ are observed to be independent of PPAR. Overexpression (wild-type and dominant-negative forms) of PPAR and its antagonist (GW9662) did not alter the 15d-PGJ₂-induced inhibition of LPS/IFN--mediated iNOS and NF-B activation. The 15d-PGJ₂ inhibited the inflammatory response by inhibiting IB kinase activity, which leads to the inhibition of degradation of IB and nuclear translocation of p65, thereby regulating the NF-B pathway. Moreover, 15d-PGJ2 also inhibited the LPS/IFN--induced PI3K-Akt pathway. The 15d-PGJ₂ inhibited the recruitment of p300 by NF-B (p65) and down-regulated the p300-mediated induction of iNOS and NF-B luciferase reporter activity. Coexpression of constitutive active Akt and PI3K (p110) reversed the 15d-PGJ₂-mediated inhibition of p300-induced iNOS and NF-B luciferase activity. This study demonstrates that 15d-PGJ₂ suppresses inflammatory response by inhibiting NF-B signaling at multiple steps as well as by inhibiting the PI3K/Akt pathway independent of PPAR in primary astrocytes.

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