miR-146a is critical for endotoxin-induced tolerance: IMPLICATION IN INNATE IMMUNITY.
The human toll-like receptor 4 (TLR4) pathway is activated in response to lipopolysaccharide (LPS), and subsequent signal transductions lead to the production of cytokines such as tumor necrosis factor-alpha (TNF-alpha) by innate immune cells. Defects in innate immune response may contribute to the overproduction of TNF-alpha leading to systemic inflammation and diseases. Thus, the innate immune response needs to be tightly regulated by elaborate mechanisms to control its onset and termination. LPS tolerance is a state of hyporesponsiveness to subsequent LPS challenge and is achieved by monocytic cells after prolonged exposure to LPS. In this report, kinetics of endotoxin-responsive microRNAs expression analysis revealed a unique pattern of gradual increase for miR-146a starting 4 h after LPS stimulation in THP-1 cells and continued up to 35-fold over 24 h. Conversely, TNF-alpha increased up to 4 h and then decreased gradually implicating a negative correlation with miR-146a progression. The characteristic up-regulation of miR-146a toward subsequent LPS challenge in THP-1 cells was studied. Strikingly, microRNA expression analysis during the tolerized state of THP-1 cells showed only miR-146a overexpression suggesting its important role in LPS tolerance. In addition, LPS tolerance was dependent on a LPS-priming dose and associated miR-146a up-regulation. LPS-tolerized cells were observed to regain responsiveness in TNF-alpha production 22 h after LPS removal correlating with a decrease in miR-146a level. Transfection of miR-146a into THP-1 cells mimicked LPS priming, whereas transfection of miR-146a inhibitor largely abolished LPS tolerance. Thus our studies demonstrated that miR-146a is critical for the in vitro monocytic cell-based endotoxin tolerance.
Department of Oral Biology, University of Florida, Gainesville, Florida 32610, USA.
Md A
MA
Nahid
Kaleb M
KM
Pauley
Minoru
M
Satoh
Edward K L
EK
Chan
D000818:Animals; D002460:Cell Line; D004731:Endotoxins / Q000276:immunology / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D004731:Endotoxins; D008070:Lipopolysaccharides; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C495345:TLR4 protein, human; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases