PKC -IRAK1 axis regulates oxidized LDL-induced IL-1 production in monocytes

Abstract

This study examined the role of interleukin (IL)-1 receptor-associated kinase (IRAK) and protein kinase C (PKC) in oxidized LDL (Ox-LDL)-induced monocyte IL-1 β production. In THP1 cells, Ox-LDL induced time-dependent secretory IL-1 β and IRAK1 activity; IRAK4, IRAK3, and CD36 protein expression; PKC β -JNK1 phosphorylation; and AP-1 activation . IRAK1/4 siRNA and inhibitor (INH)- attenuated Ox-LDL induced secreted IL-1 β and pro-IL-1 β mRNA and pro-IL-1 β and mature IL-1 β protein expression, respectively. Diphenyleneiodonium chloride (NADPH oxidase INH) and N -acetylcysteine (free radical scavenger) attenuated Ox-LDL-induced reactive oxygen species generation, caspase-1 activity, and pro-IL-1 β and mature IL-1 β expression. Ox-LDL-induced secretory IL-1 β production was abrogated in the presence of JNK INH II, Tanshinone IIa, Ro-31-8220, Go6976, Rottlerin, and PKC β siRNA. PKC β siRNA attenuated the Ox-LDL-induced increase in IRAK1 kinase activity, JNK1 phosphorylation, and AP-1 activation. In THP1 macrophages, CD36, toll-like receptor (TLR)2, TLR4, TLR6, and PKC β siRNA prevented Ox-LDLinduced PKC β and IRAK1 activation and IL-1 β production. Enhanced Ox-LDL and IL-1 β in systemic inflammatory response syndrome (SIRS) patient plasma demonstrated positive correlation with each other and with disease severity scores. Ox-LDL-containing plasma induced PKC β and IRAK1 phosphorylation and IL-1 β production in a CD36-, TLR2-, TLR4-, and TLR6-dependent manner in primary human monocytes . Results suggest involvement of CD36, TLR2, TLR4, TLR6, and the PKC β -IRAK1-JNK1- AP-1 axis in Ox-LDL-induced IL-1 β production. -Tiwari, R. L., V. Singh, A. Singh, M. Rana, A. Verma, N. Kothari, M. Kohli, J. Bogra, M. Dikshit, and M. K. Barthwal. PKC β - IRAK1 axis regulates oxidized LDL-induced IL-1 β production in monocytes. J. Lipid Res. 2014. 55: 1226 - 1244 . © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.