15-deoxy-delta 12,14-prostaglandin J2 induces heme oxygenase-1 gene expression in a reactive oxygen species-dependent manner in human lymphocytes.
15-Deoxy-delta(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 microm) 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)-gamma, 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-gamma. 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-kappaB 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-gamma 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).
Alvarez-Maqueda
Moisés
M
Departamento de Bioquímica Médica y Biología Molecular, Hospital Universitario Virgen Macarena, Universidad de Sevilla, Sevilla, Spain.
El Bekay
Rajaa
R
Alba
Gonzalo
G
Monteseirín
Javier
J
Chacón
Pedro
P
Vega
Antonio
A
Martín-Nieto
José
J
Bedoya
Francisco J
FJ
Pintado
Elisabeth
E
Sobrino
Francisco
F
D000111:Acetylcysteine / Q000494:pharmacology; D000493:Allopurinol / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003517:Cyclopentanes / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D007477:Ions; D008214:Lymphocytes / Q000201:enzymology* / Q000378:metabolism; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010618:Phenanthrolines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013696:Temperature; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D000077288:Troglitazone; D014969:Xanthine Oxidase / Q000378:metabolism / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D003497:Cyclic N-Oxides; D003517:Cyclopentanes; D007477:Ions; D008565:Membrane Proteins; D016328:NF-kappa B; D010618:Phenanthrolines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; C007201:cyclopentanone; D019328:Buthionine Sulfoximine; D000493:Allopurinol; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D014969:Xanthine Oxidase; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; D000077288:Troglitazone; D015230:Prostaglandin D2; C039671:ciglitazone; C003959:TEMPO; C025205:1,10-phenanthroline; D000111:Acetylcysteine