title: PKCδ-IRAK1 axis regulates oxidized LDL-induced IL-1β 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-1β production. In THP1 cells, Ox-LDL induced time-dependent secretory IL-1β and IRAK1 activity; IRAK4, IRAK3, and CD36 protein expression; PKCδ-JNK1 phosphorylation; and AP-1 activation. IRAK1/4 siRNA and inhibitor (INH)-attenuated Ox-LDL induced secreted IL-1β and pro-IL-1β mRNA and pro-IL-1β and mature IL-1β 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-1β and mature IL-1β expression. Ox-LDL-induced secretory IL-1β production was abrogated in the presence of JNK INH II, Tanshinone IIa, Ro-31-8220, Go6976, Rottlerin, and PKCδ siRNA. PKCδ 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 PKCδ siRNA prevented Ox-LDL-induced PKCδ and IRAK1 activation and IL-1β production. Enhanced Ox-LDL and IL-1β in systemic inflammatory response syndrome (SIRS) patient plasma demonstrated positive correlation with each other and with disease severity scores. Ox-LDL-containing plasma induced PKCδ and IRAK1 phosphorylation and IL-1β production in a CD36-, TLR2-, TLR4-, and TLR6-dependent manner in primary human monocytes. Results suggest involvement of CD36, TLR2, TLR4, TLR6, and the PKCδ-IRAK1-JNK1-AP-1 axis in Ox-LDL-induced IL-1β production.
authors.affiliation: Pharmacology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Rajiv Lochan
authors.initials: RL
authors.lastname: Tiwari
authors.affiliation: Pharmacology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Vishal
authors.initials: V
authors.lastname: Singh
authors.affiliation: Pharmacology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Ankita
authors.initials: A
authors.lastname: Singh
authors.affiliation: Pharmacology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Rana
authors.affiliation: Department of Transfusion Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Anupam
authors.initials: A
authors.lastname: Verma
authors.affiliation: Department of Anaesthesia, King George's Medical University, Lucknow, India.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Kothari
authors.affiliation: Department of Anaesthesia, King George's Medical University, Lucknow, India.
authors.forename: Monica
authors.initials: M
authors.lastname: Kohli
authors.affiliation: Department of Anaesthesia, King George's Medical University, Lucknow, India.
authors.forename: Jaishri
authors.initials: J
authors.lastname: Bogra
authors.affiliation: Pharmacology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Madhu
authors.initials: M
authors.lastname: Dikshit
authors.affiliation: Pharmacology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Barthwal
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000328:Adult; D001572:Benzofurans / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D009861:Onium Compounds / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018746:Systemic Inflammatory Response Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000074084:THP-1 Cells; D051193:Toll-Like Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000098:Acetophenones; D001572:Benzofurans; D001578:Benzopyrans; D002227:Carbazoles; C508585:IL1B protein, human; D007211:Indoles; D053583:Interleukin-1beta; D008077:Lipoproteins, LDL; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors; C099252:oxidized low density lipoprotein; C530742:tashinone IIA; C081021:Go 6976; C007517:diphenyleneiodonium; C085746:rottlerin; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta; C064758:Ro 31-8220; D000111:Acetylcysteine
keywords: inflammation; interleukin-1 receptor-associated kinase; oxidized low density lipoprotein; protein kinase Cδ