title: Interleukin-10 activates Toll-like receptor 4 and requires MyD88 for cardiomyocyte survival.
abstract: Toll-like receptors (TLRs) are important in a variety of inflammatory diseases including acute cardiac disorders. TLR4 innate signaling regulates the synthesis of anti-inflammatory cytokine, interleukin-10 (IL-10) upon TLR4 agonists' re-stimulation. Anti-apoptotic action of IL-10 in cardiac dysfunction is generally accepted but its protective mechanism through TLR4 is not yet understood. We studied the effect of IL-10 in the activation of TLR4 downstream signals leading to cardiomyocytes survival. IL-10 caused a significant increase in the expression of CD14, MyD88 and TLR4. TLR4 activation led to the translocation of the interferon regulatory factor 3 (IRF3) into the nucleus. Phosphorylation of IRF3 enhanced mRNA synthesis for IL-1β but not TNF-α and was elevated even after removal of IL-10 stimulation. Furthermore, degradation of inhibitory kappa B (IκB) kinase (Ikk) suggested that IκBβ was the main activating kinase for IRF3-regulated NF-κB activation and phosphorylation of p65. Phosphorylated NF-κB p65 was translocated into the nucleus. Concomitantly, an increase in Bcl-xL activity inhibited Bax and the proteolytic activity of caspase 3 as well as a decrease in PARP cleavage. An inhibition of MyD88, modulated the above listed responses to IL-10 as there was a decrease in TLR4 and IRF3 and an increase in TNF-α mRNA. This was associated with a decrease in NF-κB p65, Bcl-xL mRNA and protein levels as well as there was an activation of Bax and PARP cleavage independent of caspase 3 activation. These data in cardiomyocytes suggest that IL-10 induced anti-apoptotic signaling involves upregulation of TLR4 through MyD88 activation.
authors.affiliation: Institute of Cardiovascular Sciences, Department of Physiology, St. Boniface Research Centre, Faculty of Medicine, University of Manitoba, 351 Tache Avenue, Winnipeg, MB, Canada R2H 2A6.
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Bagchi
authors.forename: Anita
authors.initials: A
authors.lastname: Sharma
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Dhingra
authors.forename: Ana R
authors.initials: AR
authors.lastname: Lehenbauer Ludke
authors.forename: Abd Al-Rahman
authors.initials: AA
authors.lastname: Al-Shudiefat
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Singal
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002470:Cell Survival; D002478:Cells, Cultured; D051550:I-kappa B Kinase / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; D061945:Caspase Inhibitors; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D053583:Interleukin-1beta; D018950:Lipopolysaccharide Receptors; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D016753:Interleukin-10; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051550:I-kappa B Kinase; D053148:Caspase 3