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

Edited by Robert Barouki

Received 22 November 2007; received in revised form 6 January 2008; accepted 7 February 2008. published online 19 February 2008.

Abstract

We investigated the signaling pathway that leads to the expression of heme oxygenase-1 (HO-1) in murine macrophages in response to 15-deoxy-Δ12,14-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.

Keywords: 15-Deoxy-Δ12,14-prostaglandin J2, Heme oxygenase-1, Rac1, NADPH oxidase, p38, Nitric oxide

a Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea

b Research Institute of Life Sciences, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea

Corresponding author. Address: Department of Biochemistry and Research Institute of Life Sciences, College of Natural Sciences, Kangwon National University, 192-1 Hyoja-2-dong, Chuncheon 200-701, Republic of Korea. Fax: +82 33 242 0459.

PII: S0014-5793(08)00117-8

doi:10.1016/j.febslet.2008.02.012

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