Up-regulation of heme oxygenase-1 expression through the Rac1/NADPH oxidase/ROS/p38 signaling cascade mediates the anti-inflammatory effect of 15-deoxy-Δ12,14-prostaglandin J2 in murine macrophages

Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
FEBS Letters (Impact Factor: 3.17). 04/2008; 582(6):861-8. DOI: 10.1016/j.febslet.2008.02.012
Source: PubMed


We investigated the signaling pathway that leads to the expression of heme oxygenase-1 (HO-1) in murine macrophages in response to 15-deoxy-delta 12,14-prostaglandin J2 (15dPGJ2). 15dPGJ2 caused dose- and time-dependent activation of Rac1, followed by a transient increase in reactive oxygen species (ROS) via NADPH oxidase, which leads to downstream activation of p38 kinase. Inhibition of 15dPGJ2-dependent HO-1 expression significantly attenuated suppression by 15dPGJ2 of LPS-induced iNOS expression and subsequent production of nitric oxide (NO). Our findings strongly suggest that 15dPGJ2 exerts its anti-inflammatory activity through the Rac1-NADPH oxidase-ROS-p38 signaling to the up-regulation of HO-1 in an in vitro inflammation model.

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    • "However, the exact mechanism, by which 15d-PGJ 2 acts, is still unknown in chondrocytes. Previous reports demonstrated that, in the micromolar range, 15d-PGJ 2 induces ROS production by murine macrophages [32], human lymphocytes [33], or HepG2 hepatoma cell line [34]. However, such oxidative stress may depend on cell type since no ROS production was observed in the PCCL3 thyrocyte cell line exposed to 15d-PGJ 2 [47]. "
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    • "Additionally, 15dPGJ2 is able to activate cytoprotective mechanisms, such as the induction of HO-1 expression, in an NF-κB-independent fashion [30]. Similar results have been described by our group in human lymphocytes [32], and by other researchers in murine macrophages [65]. Therefore, accumulating evidence of 15dPGJ2 pro-inflammatory actions [22], [23], [66], [67] taken altogether makes its anti-inflammatory properties increasingly controversial [24]–[27], [31]. "
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    • "Our observations showed that only 15Δ-PGJ2 stimulated L6 cell proliferation while PGF2α and PGE2 were found to be without effect. Evidence supporting the role of 15Δ-PGJ2 in the resolution phase of inflammation is growing [45-47]; furthermore, it was shown to stimulate human fetal foreskin fibroblast proliferation [22]. In our model, the stimulating effect induced by 15Δ-PGJ2 was very significant and further underlines the importance of COX-2 activity. "
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