Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetylcysteine / pharmacology
-
Cells, Cultured
-
Colforsin / pharmacology
-
Cyclic AMP / antagonists & inhibitors
-
Cyclic AMP / metabolism
-
Endothelial Cells / cytology
-
Endothelial Cells / drug effects*
-
Endothelial Cells / metabolism
-
Enzyme-Linked Immunosorbent Assay
-
Ethacrynic Acid / pharmacology
-
Ethylmaleimide / analogs & derivatives
-
Ethylmaleimide / pharmacology
-
Gene Expression / drug effects
-
Hemin / pharmacology
-
Humans
-
Hydantoins / pharmacology
-
Interleukin-8 / genetics
-
Interleukin-8 / metabolism*
-
Oxidative Stress / drug effects*
-
Prostaglandin D2 / analogs & derivatives*
-
Prostaglandin D2 / pharmacology
-
Protein Kinase Inhibitors / pharmacology
-
RNA Stability / drug effects
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
Reactive Oxygen Species / metabolism
-
Receptors, Prostaglandin / agonists
-
Receptors, Prostaglandin / antagonists & inhibitors
-
Reverse Transcriptase Polymerase Chain Reaction
-
Superoxide Dismutase / genetics
-
Superoxide Dismutase / metabolism
-
Transfection
-
Xanthones / pharmacology
-
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
-
p38 Mitogen-Activated Protein Kinases / metabolism
Substances
-
15-deoxyprostaglandin J2
-
Hydantoins
-
Interleukin-8
-
Protein Kinase Inhibitors
-
RNA, Messenger
-
Reactive Oxygen Species
-
Receptors, Prostaglandin
-
Xanthones
-
prostanoid D receptor 1, human
-
Colforsin
-
6-isopropoxy-9-oxoxanthene-2-carboxylic acid
-
Hemin
-
BW 245C
-
Cyclic AMP
-
Superoxide Dismutase
-
p38 Mitogen-Activated Protein Kinases
-
Ethacrynic Acid
-
Ethylmaleimide
-
Prostaglandin D2
-
Acetylcysteine