15-Deoxy-Delta(12,14)-prostaglandin J(2) suppresses IL-6-induced STAT3 phosphorylation via electrophilic reactivity in endothelial cells.
In this study, the effects of 15d-PGJ(2) were investigated in IL-6-activated endothelial cells (ECs). 15d-PGJ(2) was found to abrogate phosphorylation on tyr705 of STAT3 in IL-6-treated ECs, in a dose- and time-dependent manner, but did not inhibit serine phosphorylation of STAT3 and the upperstream JAK2 phosphorylation. Other PPAR activators, such as WY1643 or ciglitazone, had no effect upon IL-6-induced STAT3 phosphorylation. Additionally, neither orthovanadate nor l-NAME treatment reverses the inhibition of STAT3 phosphorylation by 15d-PGJ(2). Otherwise, the effect of 15d-PGJ(2) requires the alpha,beta-unsaturated carbonyl group in the cyclopentane ring. A 15d-PGJ(2) analog, 9,10-Dihydro-15d-PGJ(2), which lack alpha,beta-unsaturated carbonyl group showed no increase in ROS production and no effect in inhibition of IL-6-induced STAT3 phosphorylation. The electrophilic compound, acrolein, mimics the inhibition effect of 15d-PGJ(2). Among the antioxidants, only NAC and glutathione reversed the effects of 15d-PGJ(2). NAC, glutathione and DTT all reversed the inhibition of STAT3 phosphorylation when preincubated with 15d-PGJ(2). The inhibition of ICAM-1 gene expression by 15d-PGJ(2) was abrogated by NAC and glutathione in IL-6-treated ECs. Taken together, these results suggest that 15d-PGJ(2) inhibits IL-6-stimulated phosphorylation on tyr705 of STAT3 dependent on its own electrophilic reactivity in ECs.
Wung
B S
BS
Department of Applied Microbiology, National Chiayi University, Chiayi, Taiwan. bswung@mail.ncyu.edu.tw
Wu
C C
CC
Hsu
M C
MC
Hsieh
C W
CW
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D002417:Cattle; D002478:Cells, Cultured; D004220:Disulfides / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D007155:Immunologic Factors / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000494:pharmacology; D008163:Luminescent Measurements; D009569:Nitric Oxide / Q000502:physiology; D010084:Oxidation-Reduction; D047492:Peroxisome Proliferator-Activated Receptors / Q000502:physiology; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D000975:Antioxidants; D004220:Disulfides; D007155:Immunologic Factors; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D047492:Peroxisome Proliferator-Activated Receptors; D015230:Prostaglandin D2; D017027:Protein Tyrosine Phosphatases; D012313:RNA; D050796:STAT3 Transcription Factor; D013438:Sulfhydryl Compounds; D014443:Tyrosine; D000093242:Interleukin-6 Inhibitors; C097240:15-deoxy-delta(12,14)-prostaglandin J2