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.

Automated summary

The study found that PA-BSA cooperates with LDL(-) to trigger the production of IL-1 beta in macrophages through the LOX-1 and Kv channel pathways.