Thiol antioxidant and thiol-reducing agents attenuate 15-deoxy-delta 12,14-prostaglandin J2-induced heme oxygenase-1 expression

• Published in: Life sciences (1973) 2004-03, Vol.74 (19), p.2451-2463
• Main Authors: Liu, Jean-Dean, Tsai, Shu-Huei, Lin, Shyr-Yi, Ho, Yuan-Soon, Hung, Ling-Fang, Pan, Shiann, Ho, Feng-Ming, Lin, Chun-Mao, Liang, Yu-Chih
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - metabolism; Arachidonic Acid - metabolism; Cell Line, Tumor; Dithiothreitol - metabolism; Docosahexaenoic Acids - metabolism; Eicosanoids - metabolism; Enzyme Activation; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Heme Oxygenase (Decyclizing) - genetics; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1; Humans; MAP Kinase Signaling System - physiology; Membrane Proteins; Oxidation-Reduction; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - metabolism; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - metabolism; RNA, Messenger - metabolism; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - metabolism; Transcription Factors - agonists; Transcription Factors - metabolism
• ISSN: 0024-3205

Heme oxygenase-1 (HO-1) is induced as a beneficial and adaptive response in cells and tissues exposed to oxidative stress. Herein we examined how various eicosanoids affect the induction of HO-1, and the possible mechanism underlying 15-deoxy-Delta(12,14)- prostaglandin J(2) (15d-PGJ(2))-induced HO-1 expression. PGH(2), PGD(2) and its metabolites of the PGJ(2) series, and PGA(1) markedly induced the protein expression of HO-1. Arachidonic acid (AA), docosahexaenoic acid (DHA), PGE(2), PGF(2 alpha), and thromboxane B(2) (TXB(2)) were shown to have no effect on the induction of HO-1. 15d-PGJ(2) was the most potent activator achieving significance at 5 microM. Although 15d-PGJ(2) significantly activated the MAPKs of JNK and ERK, the activation of JNK and ERK did not contribute to the induction of HO-1 as determined using transfection of dominant-negative plasmids and MAPKs inhibitors. Additional experiment indicated that 15d-PGJ(2) induced HO-1 expression through peroxisome proliferator-activated receptor (PPAR)-independent pathway. 15d-PGJ(2) significantly decreased the intracellular level of reduced glutathione; and the thiol antioxidant, N-acetyl-L-cysteine (NAC), and the thiol-reducing agent, dithiothreitol (DTT), inhibited the induction of HO-1 by 15d-PGJ(2). Finally, NAC and DTT exhibited significant inhibition of HO-1 mRNA and HO-1 promoter reporter activity induced by 15d-PGJ(2). These results suggest that thiol antioxidant and reducing agents attenuate the expression of HO-1 induced by 15d-PGJ(2), and that the cellular thiol-disulfide redox status may be linked to HO-1 activation.