title: Dynamic modulation of innate immune response by varying dosages of lipopolysaccharide (LPS) in human monocytic cells.
abstract: Innate monocytes and macrophages can be dynamically programmed into distinct states depending upon the strength of external stimuli. Innate programming may bear significant relevance to the pathogenesis and resolution of human inflammatory diseases. However, systems analyses with regard to the dynamic programming of innate leukocytes are lacking. In this study, we focused on the dynamic responses of human promonocytic THP-1 cells to lipopolysaccharide (LPS). We observed that varying dosages of LPS differentially modulate the expression of selected pro- and anti- inflammatory mediators such as IL-6 and IL-33. Super-low dosages of LPS preferentially induced the pro-inflammatory mediator IL-6, while higher dosages of LPS induced both IL-6 and IL-33. Mechanistically, we demonstrated that super-low and high doses of LPS cause differential activation of GSK3 and Akt, as well as the transcription factors FoxO1 and CREB. Inhibition of GSK3 enabled THP-1 cells to express IL-33 when challenged with super-low dose LPS. On the other hand, activation of CREB with adenosine suppressed IL-6 expression. Taken together, our study reveals a dynamic modulation of monocytic cells in response to varying dosages of endotoxin, and may shed light on our understanding of the dynamic balance that controls pathogenesis and resolution of inflammatory diseases.
authors: From the Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061 and.
authors: Matthew C
authors: MC
authors: Morris
authors: the Virginia Tech Carillion School of Medicine, Roanoke, Virginia 24016.
authors: Elizabeth A
authors: EA
authors: Gilliam
authors: From the Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061 and.
authors: Julia
authors: J
authors: Button
authors: From the Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061 and the Virginia Tech Carillion School of Medicine, Roanoke, Virginia 24016 lwli@vt.edu.
authors: Liwu
authors: L
authors: Li
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D018836:Inflammation Mediators; D008070:Lipopolysaccharides
keywords: Innate Immunity; Lipopolysaccharide (LPS); Monocyte; Systems Biology; inflammation