Caffeoyloxy-5,6-dihydro-4-methyl-(2H)-pyran-2-one isolated from the leaves of Olinia usambarensis attenuates LPS-induced inflammatory mediators by inactivating AP-1 and NF-κB

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>We have previously reported the isolation of four compounds, caffeoyloxy-5,6-dihydro-4-methyl-(2H)-pyran-2-one (CDMP), olinioside, caffeic acid and 3-hydroxylup-12-en-28-oic acid, from the leaves of <I>Olinia usambarensis</I>. Here, we evaluated the inhibitory effects of these compounds on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and prostaglandin E<SUB>2</SUB> (PGE<SUB>2</SUB>) in RAW 264.7 macrophages, and found that CDMP is the most potent of these two pro-inflammatory mediators (IC<SUB>50</SUB>; 12.12 μM and 10.78 μM, respectively). Consistent with these results, CDMP also down-regulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6) at the protein and mRNA levels in LPS-treated RAW 264.7 macrophages. Furthermore, CDMP suppressed LPS-induced nuclear factor κB (NF-κB) activation by decreasing p65 nuclear translocation through the phosphorylation and degradation of the inhibitory κBα (IκBα). CDMP also attenuated LPS-induced transcriptional and DNA-binding activities of activator protein 1 (AP-1) by suppressing the phosphorylation and expression of c-Fos and c-Jun. Finally, CDMP considerably suppressed the LPS-induced phosphorylation of c-Jun N-terminal kinase (JNK), but did not affect the phosphorylation of p38 or extracellular signal-regulated kinase (ERK). Taken together, our data suggest that CDMP down-regulates genes encoding pro-inflammatory mediators and cytokines, such as iNOS, COX-2, TNF-α, IL-1β, and IL-6 via NF-κB and JNK/AP-1 inactivation in LPS-induced RAW 264.7 macrophages.</P> <P><B>Highlights</B></P> <P> <UL> <LI> CDMP from <I>Olinia usambarensis</I> leaves suppressed LPS-induced pro-inflammatory mediators. </LI> <LI> CDMP inhibited LPS-induced NF-κB activation by blocking IκBα degradation. </LI> <LI> CDMP inhibited LPS-induced phosphorylation and nuclear expression of c-Fos and c-Jun. </LI> <LI> CDMP decreased LPS-induced JNK phosphorylation, but not p38 and JNK. </LI> <LI> CDMP is one of the active anti-inflammatory components of <I>O. usambarensis</I> leaves. </LI> </UL> </P>