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Abstract: Polyunsaturated fatty acids (PUFAs) induce COX-2 in bovine endometrial stromal cells through activation of peroxisome-proliferator-activated receptor alpha (PPARα). We have investigated alternative (PPAR-independent) pathways to COX-2 induction using a reporter construct driven by a COX-2 gene promoter sequence lacking a PPAR response element. This construct was induced by PUFAs, but not by PPAR agonists. PPAR-independent reporter gene expression occurred 6h after PPAR-dependent induction of the endogenous COX-2 gene. In contrast to PPAR-dependent COX-2 induction, which is not affected by NF-κB inhibitors, the PPAR-independent pathway was blocked by the NF-κB inhibitor MG132 or following deletion of NF-κB sites in the COX-2 promoter. The PPAR-independent effect of PUFA was mimicked by the PKC activators 4β-PMA and prostaglandin F2α, but was not blocked by the PKC inhibitor RO318425. The results demonstrate a pathway to the induction of COX-2 by PUFAs requiring NF-κB but not PPAR or PKC. [Copyright &y& Elsevier]