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PKC -IRAK1 axis regulates oxidized LDL-induced IL-1 production in monocytesRajiv Lochan Tiwari,1,* Vishal Singh,1,* Ankita Singh,1,* Minakshi Rana,* Anupam Verma, Nikhil Kothari,Monica Kohli,Jaishri Bogra,Madhu Dikshit,* and Manoj Kumar Barthwal2,*Pharmacology Division,* Council of Scientific and Industrial Research-Central Drug Investigation Institute, Lucknow, India; Department of Transfusion Medicine, Sanjay Gandhi Postgraduate Institute of Health-related Sciences, Lucknow, India; and Division of Anaesthesia,King George’s Healthcare University, Lucknow, IndiaAbstract 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.Indole Description Diphenyleneiodonium chloride (NADPH oxidase INH) and N-acetylcysteine (cost-free radical scavenger) attenuated Ox-LDL-induced reactive oxygen species generation, caspase-1 activity, and pro-IL-1 and mature IL-1 expression.HEPES Biochemical Assay Reagents Ox-LDL-induced secretory IL-1 production was abrogated within the presence of JNK INH II, Tanshinone IIa, Ro-31-8220, Go6976, Rottlerin, and PKC siRNA.PMID:23775868 PKC siRNA attenuated the Ox-LDL-induced raise in IRAK1 kinase activity, JNK1 phosphorylation, and AP-1 activation. In THP1 macrophages, CD36, toll-like receptor (TLR)two, TLR4, TLR6, and PKC siRNA prevented Ox-LDLinduced PKC and IRAK1 activation and IL-1 production. Enhanced Ox-LDL and IL-1 in systemic inflammatory response syndrome (SIRS) patient plasma demonstrated optimistic correlation with every single other and with illness severity scores. Ox-LDL-containing plasma induced PKC and IRAK1 phosphorylation and IL-1 production within a CD36-, TLR2-, TLR4-, and TLR6-dependent manner in main human monocytes. Benefits recommend involvement of CD36, TLR2, TLR4, TLR6, and also the PKC -IRAK1-JNK1AP-1 axis in Ox-LDL-induced IL-1 production.–Tiwari, R. L., V. Singh, A. Singh, M. Rana, A. Verma, N. Kothari, M. Kohli, J. Bogra, M. Dikshit, and M. K. Barthwal. P.
