15-Deoxy-Δ12,14-prostaglandin J2 Induces Heme Oxygenase-1 Gene Expression in a Reactive Oxygen Species-dependent Manner in Human Lymphocytes

• Published in: The Journal of biological chemistry Vol. 279; no. 21; p. 21929
• Main Authors: Moisés Álvarez-Maqueda, Rajaa El Bekay, Gonzalo Alba, Javier Monteseirín, Pedro Chacón, Antonio Vega, José Martín-Nieto, Francisco J. Bedoya, Elisabeth Pintado, Francisco Sobrino
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 21.05.2004
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M400492200

15-Deoxy-Δ 12,14 -prostaglandin J 2 (15dPGJ 2 has been recently proposed as a potent anti-inflammatory agent. However, the mechanisms by which 15dPGJ 2 mediates its therapeutic effects in vivo are unclear. We demonstrate that 15dPGJ 2 at micromolar (2.5–10 μ m ) concentrations induces the expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme, at both mRNA and protein levels in human lymphocytes. In contrast, troglitazone and ciglitazone, two thiazolidinediones that mimic several effects of 15dPGJ 2 through their binding to the peroxisome proliferator-activated receptor (PPAR)-γ, did not affect HO-1 expression, and the positive effect of 15dPGJ 2 on this process was mimicked instead by other cyclopentenone prostaglandins (PG), such as PGD 2 (the precursor of 15dPGJ 2 ) and PGA 1 and PGA 2 which do not interact with PPAR-γ. Also, 15dPGJ 2 enhanced the intracellular production of reactive oxygen species (ROS) and increased xanthine oxidase activity in vitro . Inhibition of intracellular ROS production by N -acetylcysteine, TEMPO, Me 2 SO, 1,10-phenanthroline, or allopurinol resulted in a decreased 15dPGJ 2 -dependent HO-1 expression in the cells. Furthermore, buthionine sulfoximine, an inhibitor of reduced glutathione synthesis, or Fe 2+ /Cu 2+ ions enhanced the positive effect of 15dPGJ 2 on HO-1 expression. On the other hand, the inhibition of phosphatidylinositol 3-kinase or p38 mitogen-activated protein kinase, or the blockade of transcription factor NF-κB activation, hindered 15dPGJ 2 -elicited HO-1 expression. Collectively, the present data suggest that 15dPGJ 2 anti-inflammatory actions at pharmacological concentrations involve the induction of HO-1 gene expression through mechanisms independent of PPAR-γ activation and dependent on ROS produced via the xanthine/xanthine oxidase system and/or through Fenton reactions. Both phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase signaling pathways also appear implicated in modulation of HO-1 expression by 15dPGJ 2 .