Supression of the expression of cyclooxygenase-2 by ozonides of oleate ester

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Ozonized olive oil has been reported to exert anti-inflammatory effect. However, the details of chemical structure of ozonized olive oil and its action mechanism have long been unclear. We have recently demonstrated that the major component of the ozonized olive oil is triozonide of triolein. In this study, we identified several minor components of ozonized olive oil, including "cross ozonides" of low and high molecular weight. In addition, to elucidate the anti-inflammatory action mechanism of ozonized olive oil, we investigated the effects of ozonized olive oil and methyl oleate ozonides on the generation of PGE_2 and the expression of Cyclooxygenase-2 (COX-2) in Lipopolysaccharide (LPS)-stimulated macrophage-like THP-1 cells. Olive oil, methyl oleate and their ozonides did not affect cell viability and morphology within a concentration used. LPS-induced COX-2 expression and PGE_2 generation in macrophage-like THP-1 cells were not affected by olive oil itself. However, ozonized olive oil inhibited both reactions in a concentration-dependent manner. Methyl oleate ozonides also inhibited COX-2 expression and PGE_2 generation whereas oleic acid and methyl oleate did not show such inhibitory effects. Such actions of ozonized olive oil and methyl oleate ozonide were shown to be due to their inhibitory effect on lкB phosphorylation which is required for Nuclear factor-kappa B (NFкB) activation and subsequent COX-2 gene transcription in LPS-stimulated macrophages. The inhibitory effect was also observed with ozonide having no functional group except for ozonide ring. In addition, ozonized olive oil and methyl oleate ozonide showed no effect on the phosphorylations of p38 and JNK, which are involved in the activation of AP-1. These results demonstrate that ozonized olive oil and methyl oleate ozonides suppress LPS-induced PGE_2 generation in macrophage-like THP-1 cells through inhibition of COX-2 gene transcription by suppressing the lкBαNFкB pathway.