Thiol antioxidant and thiol-reducing agents attenuate 15-deoxy-delta 12,14-prostaglandin J2-induced heme oxygenase-1 expression.
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.
Liu
Jean-Dean
JD
College of Medicine, Taipei Medical University, Taipei, Taiwan. ycliang@tmu.edu.tw
Tsai
Shu-Huei
SH
Lin
Shyr-Yi
SY
Ho
Yuan-Soon
YS
Hung
Ling-Fang
LF
Pan
Shiann
S
Ho
Feng-Ming
FM
Lin
Chun-Mao
CM
Liang
Yu-Chih
YC
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D045744:Cell Line, Tumor; D004229:Dithiothreitol / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins; D010084:Oxidation-Reduction; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000975:Antioxidants; D015777:Eicosanoids; D008565:Membrane Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D015230:Prostaglandin D2; D004229:Dithiothreitol