Abstract 258: Oxidized LDL-Induced Upregulation of IL-18 in Monocytes/Macrophages is Modulated by Lipoprotein-Associated Phospholipase A2 – Potential Mechanism of Inflammatory Burden in Atherosclerosis
Background. Both IL-18 and Lp-PLA2 are markers of cardiovascular risk, we explored the role of Lp-PLA2 in the regulation of IL-18 in monocytes and macrophages.
Method and Results. Expression of IL-18 and Lp-PLA2 was assessed in atherosclerotic plaque and peripheral blood mononuclear cells (PBMC) derived from healthy blood donors (Donor, n=19) and from patients undergoing carotid endarterectomy (CEA, n=54). Microarray analysis revealed a 3.7-fold increase in IL-18 expression in CEA plaques compared with normal vessels (Table⇓). Of note, IL-18 was closely correlated with Lp-PLA2 expression (r=0.72, p<0.01). Using real time RT-PCR, similar findings were obtained from PBMC derived from CEA patients (Table⇓, r=0.54, p<0.01). To explore mechanisms underlying augmented expression of IL-18, PBMC and macrophages were stimulated with oxLDL in presence or absence of an Lp-PLA2 inhibitor. OxLDL significantly augmented IL-18 expression. When Lp-PLA2 inhibitor (SB677116) was present, however, oxLDL-induced IL-18 was attenuated (oxLDL: 1.08±0.13 vs oxLDL+inhibitor: 0.72±0.01 pg/mg, p<0.05). To confirm the role of Lp-PLA2, PBMC and macrophages were exposed to lyso-PC, product of oxLDL generated by Lp-PLA2. A concentration-dependent upregulation of IL-18 was observed (p<0.01). As IL-18 was augmented in CEA plaque, the effects of the Lp-PLA2 inhibitor were also determined in an ex vivo organ culture of CEA plaques (n=21). In parallel with reduced Lp-PLA2 activity, IL-18 in CEA plaques was reduced by Lp-PLA2 inhibitor (191.4±21.5 vs. 130.7±18.1 pg/mg, p<0.05).
Conclusions: 1. IL-18 expression is increased in PBMC and plaque macrophages in CEA patients. 2. Oxidized LDL augmented IL-18 expression in PBMC and macrophages, which was attenuated by inhibition of Lp-PLA2 in modified LDL. 3. Our findings suggest that Lp-PLA2, an emerging cardiovascular risk marker, has the potential to modulate systemic and plaque inflammation.