15-Deoxy-{delta}12,14-prostaglandin j2 inhibits interleukin-1{beta}-induced nuclear factor-{kappa}b in human amnion and myometrial cells: mechanisms and implications.
Proinflammatory cytokines and prostaglandins play key roles in term and preterm human labor. The expression of the prostaglandin synthetic enzyme cyclooxygenase (COX)-2 and cytokines IL-1beta and IL-8 increases within the uterus at the time of labor, and each is regulated by the transcription factor nuclear factor-kappaB (NF-kappaB). In addition to its role in driving inflammation, COX-2 may also synthesize 15-deoxy-Delta (12, 14)-prostaglandin J(2) (15d-PGJ(2)), an antiinflammatory cyclopentenone prostaglandin (cyPG), which acts in some cells as an agonist of peroxisome proliferator-activated receptors (PPARs). We found that PPARalpha and -gamma proteins are expressed in both amnion epithelial and myometrial cells, but synthetic PPAR agonists could not inhibit NF-kappaB activity or COX-2 expression. 15d-PGJ(2) inhibited NF-kappaB activity and COX-2 expression in both cell types. This was unaffected by a PPAR antagonist and could be mimicked by the cyPG PGA(1) but not 9,10-dihydro-15d-PGJ(2) in which the cyclopentenone ring is disrupted. This shows that, in amnion and myometrium, inhibition of NF-kappaB activity and COX-2 expression by 15d-PGJ(2) is independent of PPARs and requires the cyclopentenone ring. We further show that 15d-PGJ(2) acts at multiple levels in the NF-kappaB pathway: blocking inhibitor of kappaBalpha degradation by repressing inhibitor of kappaB kinase activation and the 26S proteasome and also repressing NF-kappaB DNA binding and phosphorylation. Our data suggest that PPARs are unlikely to play a role in the regulation of either NF-kappaB or COX-2 in human amnion and myometrium. Targeting of NF-kappaB is a potential therapeutic strategy in preterm labor. PPAR agonists are unlikely to be effective in this context, but cyPGs may have potential.
Lindström
Tamsin M
TM
Hammersmith Campus, Imperial College, Du Cane Road, London W12 0NN, United Kingdom. t.lindstrom@imperial.ac.uk
Bennett
Phillip R
PR
D000650:Amnion / Q000166:cytology / Q000502:physiology*; D002585:Cesarean Section; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D009215:Myometrium / Q000166:cytology / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D050811:Octamer Transcription Factor-1; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000502:physiology; D011247:Pregnancy; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D017931:DNA Primers; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D047492:Peroxisome Proliferator-Activated Receptors; D014157:Transcription Factors; D015230:Prostaglandin D2