Absolute and induction TNF tolerance in primary human monocytes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE45371 | GEO | 2014/02/11
SECONDARY ACCESSION(S): PRJNA193569
REPOSITORIES: GEO
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Project description:The molecular basis of TNF tolerance is poorly understood. In this experiment, primary human monocytes were used to examine TNF refractoriness. We detect absolute tolerance as selective, dose-dependently affecting a small group of powerful effector molecules; induction tolerance represented a more general phenomenon. Primary human monocytes were incubated for 48 h with Medium or different TNF-doses and subsequently short-term stimulated for two hours with TNF. Total RNA was prepared and analysed by use of Agilent microarrays. 6 different conditions were analyzed in total, corresponding to cells that were: 1) medium incubated (M+M), 2) medium incubated and short time TNF (400 U/ml) incubated (M+T), 3) low dose TNF (40 U/ml) preincubated (40+M), 4) low dose TNF preincubated and short time TNF incubated (40+T), 5) high dose TNF (400 U/ml) preincubated (400+M), 6) high dose TNF preincubated and short time TNF incubated (400+T). 3 biological replicates (corresponding to three different healthy donors) were analyzed regarding high-dose tolerance conditions (preincubation with 400 U TNF/ml), one of which was analyzed in duplicates (including cell culture, RNA preparation and a dye-swap microarray approach). 2 biological replicates (corresponding to two different healthy donors) were analyzed under low-dose tolerance conditions (preincubation with 40 U/ml). The different human donors were numbered and indicated in brackets (d1-d5).
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Project description:Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge. Training and priming are important for innate memory responses that protect against infection, efficacy of vaccines, and maintaining innate immune cells in a state of readiness; tolerance prevents toxicity from excessive immune activation. Dysregulation of these processes can contribute to pathogenesis of autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis- associated immunoparalysis. Training, priming and tolerance regulate similar ‘signature’ inflammatory genes such as TNF, IL6 and IL1B and utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known for activating Jak-STAT signaling and interferon- stimulated genes, also play a key role regulating training, priming and tolerance via chromatin- mediated mechanisms. We present new data on how monocyte-to-macrophage differentiation modulates IFN-g-mediated priming, changes AP-1 and CEBP activity, and attenuates superinduction of inflammatory genes. We present a ‘training-priming continuum’ model that integrates IFN-mediated priming into current concepts about training and tolerance and proposes a central role for STAT1 and IRF1.
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Project description:Absolute and induction TNF tolerance in primary human monocytes
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