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15-Deoxy-^12,14-Prostaglandin J₂ Inhibits Interleukin-1ß-Induced Nuclear Factor-B in Human Amnion and Myometrial Cells: Mechanisms and Implications

Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College, London NW12 0NN, United Kingdom

Address all correspondence and requests for reprints to: Tamsin M. Lindström, 3rd Floor IRDB, Hammersmith Campus, Imperial College, Du Cane Road, London W12 0NN, United Kingdom. E-mail: t.lindstrom{at}imperial.ac.uk.

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-1ß and IL-8 increases within the uterus at the time of labor, and each is regulated by the transcription factor nuclear factor-B (NF-B). In addition to its role in driving inflammation, COX-2 may also synthesize 15-deoxy- (12, 14)-prostaglandin J₂ (15d-PGJ₂), an antiinflammatory cyclopentenone prostaglandin (cyPG), which acts in some cells as an agonist of peroxisome proliferator-activated receptors (PPARs).

We found that PPAR and - proteins are expressed in both amnion epithelial and myometrial cells, but synthetic PPAR agonists could not inhibit NF-B activity or COX-2 expression. 15d-PGJ₂ inhibited NF-B activity and COX-2 expression in both cell types. This was unaffected by a PPAR antagonist and could be mimicked by the cyPG PGA₁ but not 9,10-dihydro-15d-PGJ₂ in which the cyclopentenone ring is disrupted. This shows that, in amnion and myometrium, inhibition of NF-B activity and COX-2 expression by 15d-PGJ₂ is independent of PPARs and requires the cyclopentenone ring. We further show that 15d-PGJ₂ acts at multiple levels in the NF-B pathway: blocking inhibitor of B degradation by repressing inhibitor of B kinase activation and the 26S proteasome and also repressing NF-B DNA binding and phosphorylation.

Our data suggest that PPARs are unlikely to play a role in the regulation of either NF-B or COX-2 in human amnion and myometrium. Targeting of NF-B is a potential therapeutic strategy in preterm labor. PPAR agonists are unlikely to be effective in this context, but cyPGs may have potential.

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