Effects of LPS-mediated bystander activation in the innate immune system.
LPS induces dendritic cell (DC) activation, but the precise in vivo mechanism is unclear since DCs express low levels of TLR4. Here, it is shown that DCs can be activated in response to LPS through a bystander mechanism. This result was obtained using chimeric mice reconstituted with LPS-responsive and nonresponsive bone marrow cells. Thus, after indirect in vivo conditioning by LPS, bystander-activated DCs (LPS nonresponsive) up-regulated CD86. This up-regulation occurred even when LPS-responsive cells were MyD88 deficient. Functional analysis demonstrated that in vivo LPS conditioning endowed both the LPS-responsive and bystander cells with the ability to produce IFN-gamma in response to TLR9 stimulation in vitro. IFN-gamma production was also shown to be important for enhanced T-bet gene expression but not important for up-regulation of CD86. To investigate aspects of the mechanism, we used intracellular cytokine staining and found that NKDCs were responsible for at least some of the IFN-gamma production. Thus, our in vivo results demonstrated that bacterial LPS can bridge activation of various cellular populations of the innate immune system through a bystander mechanism.
Yadav
Rajwardhan
R
University of Connecticut Health Center, 263 Farmington Ave., MC1319, Farmington, CT 06030, USA.
Zammit
David J
DJ
Lefrancois
Leo
L
Vella
Anthony T
AT
D000818:Animals; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D024201:Bystander Effect / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000098815:T-bet Transcription Factor
D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma