Di Somma, Sarah (2018) GM-CSF and IL-3 Modulate Human Monocyte TNF-A Production and Renewal in In Vitro Models of Trained Immunity. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: GM-CSF and IL-3 Modulate Human Monocyte TNF-A Production and Renewal in In Vitro Models of Trained Immunity
Creators:
CreatorsEmail
Di Somma, Sarahsarah.ds@libero.it
Date: 11 December 2018
Number of Pages: 60
Institution: Università degli Studi di Napoli Federico II
Department: Scienze Mediche Traslazionali
Dottorato: Medicina clinica e sperimentale
Ciclo di dottorato: 31
Coordinatore del Corso di dottorato:
nomeemail
Beguinot, Francescobeguino@unina.it
Tutor:
nomeemail
Portella, GiuseppeUNSPECIFIED
Date: 11 December 2018
Number of Pages: 60
Uncontrolled Keywords: Innate Immune Memory, Inflammation, Monocyte.
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/05 - Patologia clinica
Date Deposited: 07 Jan 2019 08:08
Last Modified: 18 Jun 2020 05:14
URI: http://www.fedoa.unina.it/id/eprint/12621

Abstract

GM-CSF and IL-3 are hematopoietic cytokines that modulate the effector functions of several immune cell subsets. In particular, GM-CSF and IL-3 exert a significant control on monocyte and macrophage effector functions, as assessed in experimental models of inflammatory and autoimmune diseases and in human studies. Here we sought to investigate the mechanisms and the extent to which GM-CSF and IL-3 modulate the pro-inflammatory, LPS-mediated, activation of human CD14+ monocytes taking into account the new concept of trained immunity (i.e. the priming stimulus modulates the response to subsequent stimuli mainly by enhancing immune activation status). We demonstrate that GM-CSF and IL-3 priming enhances TNF-α production upon subsequent LPS stimulation (short-term model of trained immunity) in a p38- and SIRT2-dependent manner without increasing TNF mRNA or primary transcript levels (a more direct measure of transcription), thus supporting a post-transcriptional regulation of TNF- α in primed monocytes. GM-CSF and IL-3 priming followed by 6 days of resting also results in increased TNF-α production upon LPS stimulation (long-term model of trained immunity). In this case, however, GM-CSF and IL-3 priming induces a c-Myc-dependent monocyte renewal and increase in cell number that is in turn responsible for heightened TNF-α production. Overall, our results provide insights to understand the biology of monocytes in health and disease conditions in which the hematopoietic cytokines GM-CSF and IL-3 play a role and also extend our knowledge of the cellular and molecular mechanisms of trained immunity.

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