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? production. In THP1 cells, Ox-LDL induced time-dependent secretory IL-1? and IRAK1 activity; IRAK4, IRAK3, and CD36 protein expression; PKC?-JNK1 phosphorylation; and AP-1 activation. IRAK1/4 siRNA and inhibitor (INH)-attenuated Ox-LDL induced secreted IL-1? and pro-IL-1? mRNA and pro-IL-1? and mature IL-1? 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? and mature IL-1? expression. Ox-LDL-induced secretory IL-1? production was abrogated in the presence of JNK INH II, Tanshinone IIa, Ro-31-8220, Go6976, Rottlerin, and PKC? siRNA. PKC? 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? siRNA prevented Ox-LDL-induced PKC? and IRAK1 activation and IL-1? production. Enhanced Ox-LDL and IL-1? 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? and IRAK1 phosphorylation and IL-1? 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?-IRAK1-JNK1-AP-1 axis in Ox-LDL-induced IL-1? production.

SUBMITTER: Tiwari RL 

PROVIDER: S-EPMC4076070 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature