Synergistic effects of electronegative-LDL- and palmitic-acid-triggered IL-1,6 production in macrophages via LOX-1-and voltage-gated-potassium-channel-dependent pathways

Electronegative LDL (LDL(-)) and free fatty acids (FFAs) are circulating risk factors for cardiovascular diseases (CVDs) and have been associated with inflammation. Interleukin-1 beta (IL-1 beta) represents a key cytokine in the development of CVD; however, the initial trigger of IL-1 beta in CVD remains to be explored. In this study, we investigated the combined effects of LDL(-) from the plasma of ST-segment elevation myocardial infarction (STEMI) patients or diet-induced hypercholesterolemic rabbits and bovine serum albumin bound palmitic acid (PA-BSA) on IL-1 beta production in macrophages. Macrophages derived from THP-1 cells or human peripheral blood mononuclear cells were independently treated with LDL(-), PA-BSA or cotreated with LDL(-) and PA BSA. The results showed that nLDL and/or PA-BSA had no effect on IL-1 beta, and LDL(-) slightly increased IL-1 beta; however, cotreatment with LDL(-) and PA-BSA resulted in abundant secretion of IL-1 beta in macrophages. Rabbit LDL(-) induced the elevation of cellular pro-IL-1 beta and p-IK-Ba , but PA-BSA had no effect on pro-IL-1 beta or p-IK-Ba. In potassium-free buffer, LDL(-)-induced IL-1 beta reached a level similar to that induced by cotreatment with LDL(-) and PA-BSA. Moreover, LDL(-) and PA-BSA-induced IL-1 beta was inhibited in lectin-type oxidized LDL receptor-1 (LOX-1) knockdown cells and by blockers of voltage-gated potassium (Kv) channels. LDL(-) from diet-induced hypercholesterolemic rabbit had a similar effect as STEMI LDL(-) on IL-1 beta in macrophages. These results show that PA-BSA cooperates with LDL(-) to trigger IL-1 beta production in macrophages via a mechanism involving the LOX-1 and Kv channel pathways, which may play crucial roles in the regulation of inflammation in CVD. (C) 2021 The Author(s). Published by Elsevier Inc.