15d-PGJ2 upregulates synthesis of IL-8 in endothelial cells through induction of oxidative stress.
15-Deoxy-Delta(12,14)-prostaglandin-J(2) (15d-PGJ(2)) is a cyclopentenone prostaglandin regarded as antiinflammatory mediator, which can act through peroxisome proliferator-activated receptor-gamma (PPARgamma) or through G protein-coupled surface receptors. It has been demonstrated that 15d-PGJ(2) potently increases the generation of interleukin-8 (IL-8) in human microvascular endothelial cells (HMEC-1s); however, the mechanism of this induction is not known. The aim of the study was to find the pathway involved in 15d-PGJ(2)-mediated IL-8 stimulation. Our data confirmed that the effect of 15d-PGJ(2) is independent of PPARgamma. For the first time, we excluded the activation of G proteins and the contribution of G protein-coupled surface receptors in endothelial cells treated with 15d-PGJ(2). Instead, we demonstrated that stimulation of IL-8 involved induction of oxidative stress, activation of p38 kinases, and increase in stability of IL-8 mRNA. Upregulation of IL-8 promoter, although measurable, seemed to play a less-pronounced role. Additionally, our results indicate the involvement of cAMP elevation and may suggest a role for ATF2 transcription factor. Concomitant induction of heme oxygenase-1 in HMEC-1s did not influence the synthesis of IL-8. In summary, we showed that 15d-PGJ(2), acting through oxidative stress, may exert proinflammatory effects. The upregulation of IL-8 is mostly associated with p38-mediated stabilization of mRNA.
Jozkowicz
Alicja
A
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow, Poland. alicia@mol.uj.edu.pl
Was
Halina
H
Taha
Hevidar
H
Kotlinowski
Jerzy
J
Mleczko
Katarzyna
K
Cisowski
Jaroslaw
J
Weigel
Guenter
G
Dulak
Jozef
J
D000111:Acetylcysteine / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004976:Ethacrynic Acid / Q000494:pharmacology; D005033:Ethylmaleimide / Q000031:analogs & derivatives / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D044004:Xanthones / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
C477819:15-deoxyprostaglandin J2; D006827:Hydantoins; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011982:Receptors, Prostaglandin; D044004:Xanthones; C501562:prostanoid D receptor 1, human; D005576:Colforsin; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D006427:Hemin; C030669:BW 245C; D000242:Cyclic AMP; D013482:Superoxide Dismutase; D048051:p38 Mitogen-Activated Protein Kinases; D004976:Ethacrynic Acid; D005033:Ethylmaleimide; D015230:Prostaglandin D2; D000111:Acetylcysteine