An in vitro Shwartzman reaction-like response is augmented age-dependently in human peripheral blood mononuclear cells

Motegi, Akira; Kinoshita, Manabu; Sato, Kengo; Shinomiya, Nariyoshi; Ono, Satoshi; Nonoyama, Shigeaki; Hiraide, Hoshio; Seki, Shu

doi:10.1189/jlb.0705396

Cited by 24 publications

(32 citation statements)

References 55 publications

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“…Although the phenomena of endotoxin tolerance and priming triggered by a short period of single dose LPS challenge have been well documented (19–21), limited studies are performed to characterize the adaptation effects of prolonged LPS exposures on monocytes. In this context, we assessed the gene expression profiles of murine monocytes continuously challenged with varying dosages of LPS for a 5-day period.…”

Section: Resultsmentioning

confidence: 99%

Molecular Mechanisms That Underlie the Dynamic Adaptation of Innate Monocyte Memory to Varying Stimulant Strength of TLR Ligands

Yuan

Geng

2016

Front. Immunol.

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In adaptation to rising stimulant strength, innate monocytes can be dynamically programed to preferentially express either pro- or anti-inflammatory mediators. Such dynamic innate adaptation or programing may bear profound relevance in host health and disease. However, molecular mechanisms that govern innate adaptation to varying strength of stimulants are not well understood. Using lipopolysaccharide (LPS), the model stimulant of toll-like-receptor 4 (TLR4), we reported that the expressions of pro-inflammatory mediators are preferentially sustained in monocytes adapted by lower doses of LPS, and suppressed/tolerized in monocytes adapted by higher doses of LPS. Mechanistically, monocytes adapted by super-low dose LPS exhibited higher levels of transcription factor, interferon regulatory factor 5 (IRF5), and reduced levels of transcriptional modulator B lymphocyte-induced maturation protein-1 (Blimp-1). Intriguingly, the inflammatory monocyte adaptation by super-low dose LPS is dependent upon TRAM/TRIF but not MyD88. Similar to LPS, we also observed biphasic inflammatory adaptation and tolerance in monocytes challenged with varying dosages of TLR7 agonist. In sharp contrast, rising doses of TLR3 agonist preferentially caused inflammatory adaptation without inducing tolerance. At the molecular level, the differential regulation of IRF5 and Blimp-1 coincides with unique monocyte adaptation dynamics by TLR4/7 and TLR3 agonists. Our study provides novel clue toward the understanding of monocyte adaptation and memory toward distinct TLR ligands.

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Section: Resultsmentioning

confidence: 99%

Molecular Mechanisms That Underlie the Dynamic Adaptation of Innate Monocyte Memory to Varying Stimulant Strength of TLR Ligands

Yuan

Geng

2016

Front. Immunol.

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“…The discovery that higher initial doses can mitigate the TNF-a response to secondary challenge is suggestive of a dose-dependent mechanism governing the shift between priming and tolerance. Priming of lymphocytes with interleukin 12 (IL-12) has also been shown to result in increased TNF-a upon LPS exposure, acting through IFN-c (Motegi et al 2006). A 1996 experiment showed that pretreatment of mouse macrophages with LPS at approximately 0.1 ng/mL resulted in a huge spike in IL-6 and TNF-a production upon secondary stimulation by a higher dose.…”

Section: The Priming Effects Of Super Low Dose Lpsmentioning

confidence: 99%

“…The Shwartzman-like reaction has been well documented, but generally in vivo, with little molecular-level work having been done since the 1990s. Indeed, the phenomenon appears to have been largely overlooked, relegated to the status of a clinical curiosity useful only as a disease model for other conditions (Berg et al 1995;Heremans et al 1990;Motegi et al 2006;Rocksén et al 2004;Slofstra et al 2006). The mechanisms governing the decision between a Shwartzman-like or tolerogenic response have been largely unexplored, with existing research on the subject having turned up a labyrinthine tangle of signaling cascades.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms and Pathological Consequences of Endotoxin Tolerance and Priming

Morris

2011

Arch. Immunol. Ther. Exp.

102

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Lipopolysaccharide (LPS), a component of Gram-negative bacteria, is a potent inflammatory stimulant, with high doses due to disseminated bacterial infection resulting in systemic inflammatory response syndrome and death. Lower doses can induce a state of tolerance to subsequent toxic doses of LPS, but extremely low doses have an opposite effect, priming the immune system for an even more violent response to subsequent challenge. A substantial body of research exists on the phenomenon of endotoxin tolerance, which appears to be a state of generalized dampening of inflammatory pathways. Comparatively little is known about the mechanisms or indeed the phenomenon of priming, particularly regarding the shift from a priming to a tolerizing response. Our aim is to review recent findings in the field of the inflammatory response to endotoxin, with a focus on highlighting the gaps in current understanding and attempting to reconcile the competing tolerance and priming phenomena.

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“…It also prevents mice from developing either generalized Shwartzman reaction or multi-organ failure induced by consecutive injection of IL-12 and LPS into mice by inhibiting TNF production [5]. Shwartzman reaction-like response was also reproduced by human PBMCs in vitro [6]. …”

Section: Introductionmentioning

confidence: 99%

The Effect of Synthetic C-Reactive Protein on the In Vitro Immune Response of Human PBMCs Stimulated with Bacterial Reagents

et al. 2013

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Synthetic C-reactive protein (CRP) rescues mice from lethal endotoxin shock or bacterial infection by suppressing tumor necrosis factor (TNF-α), but in turn, enhances Kupffer cell phagocytic activity. We herein assessed the influence of CRP in human peripheral blood mononuclear cells (PBMCs). When human PBMCs were stimulated in vitro with penicillin-treated Streptococcus pyogenes, bacterial DNA motifs and lipopolysaccharide with or without synthetic CRP, CRP suppressed the production of TNF-α and IL-12, but not that of IFN-γ. This was also the case for the in vitro Shwartzman reaction induced in PBMCs. CRP also decreased high-mobility group box 1 production from macrophages, which is crucial in the later phase of endotoxin/septic shock. However, CRP upregulated the perforin expression by CD56+ NK cells and increased their antitumor cytotoxicity. CRP may thus be a potent immunomodulatory factor in the human immune system, suggesting its therapeutic potential for use against human septic shock.

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An in vitro Shwartzman reaction-like response is augmented age-dependently in human peripheral blood mononuclear cells

Cited by 24 publications

References 55 publications

Molecular Mechanisms That Underlie the Dynamic Adaptation of Innate Monocyte Memory to Varying Stimulant Strength of TLR Ligands

Molecular Mechanisms That Underlie the Dynamic Adaptation of Innate Monocyte Memory to Varying Stimulant Strength of TLR Ligands

Molecular Mechanisms and Pathological Consequences of Endotoxin Tolerance and Priming

The Effect of Synthetic C-Reactive Protein on the In Vitro Immune Response of Human PBMCs Stimulated with Bacterial Reagents

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