The inhibitory effect of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) on proinflammatory gene expression has been extensively documented and frequently ascribed to its ability to prevent NF-kappa B pathway activation. We and others have previously demonstrated that it was frequently independent of the peroxisome proliferator activated receptor (PPAR)gamma activation. Here, we provide evidence that induction of intracellular heat shock protein (HSP)70 by oxidative stress is an additional regulatory loop supporting the anti-inflammatory effect of 15d-PGJ(2) in chondrocytes. Using real-time quantitative PCR and Western blotting, we showed that 15d-PGJ(2) stimulated HSP70, but not HSP27 expression while increasing oxidative stress as measured by spectrofluorimetry and confocal spectral imaging. Using N-acetylcysteine (NAC) as an antioxidant, we demonstrated further that oxidative stress was thoroughly responsible for the increased expression of HSP70. Finally, using an HSP70 antisense strategy, we showed that the inhibitory effect of 15d-PGJ(2) on IL-1-induced activation of the NF-kappa B pathway, COX-2 and mPGES-1 expression, and PGE(2) synthesis was partly supported by HSP70. These data provide a new anti-inflammatory mechanism to support the PPAR gamma-independent effect of 15d-PGJ(2) in chondrocyte and suggest a possible feedback regulatory loop between oxidative stress and inflammation via intracellular HSP70 up-regulation. This cross talk is consistent with 15d-PGJ(2) as a putative negative regulator of the inflammatory reaction. (C) 2014 Elsevier Inc. All rights reserved.