Transcriptional regulation of suppressors of cytokine signaling during infection with Mycobacterium tuberculosis in human THP-1-derived macrophages and in mice
Copyright © 2023 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved..
Mycobacterium tuberculosis (Mtb) infection leads to upregulation of Suppressors of Cytokine signaling (SOCS) expression in host macrophages (Mϕ). SOCS proteins inhibit cytokine signaling by negatively regulating JAK/STAT. We investigated this host-pathogen dialectic at the level of transcription. We used phorbol-differentiated THP-1 Mϕ infected with Mtb to investigate preferential upregulation of some SOCS isoforms that are known to inhibit signaling by IFN-γ, IL-12, and IL-6. We examined time kinetics of likely transcription factors and signaling molecules upstream of SOCS transcription, and survival of intracellular Mtb following SOCS upregulation. Our results suggest a plausible mechanism that involves PGE2 secretion during infection to induce the PKA/CREB axis, culminating in nuclear translocation of C/EBPβ to induce expression of SOCS1. Mtb-infected Mϕ secreted IL-10, suggesting a mechanism of induction of STAT3, which may subsequently induce SOCS3. We provide evidence of temporal variation in SOCS isoform exspression and decay. Small-interfering RNA-mediated knockdown of SOCS1 and SOCS3 restored the pro-inflammatory milieu and reduced Mtb viability. In mice infected with Mtb, SOCS isoforms persisted across Days 28-85 post infection. Our results suggest that differential temporal regulation of SOCS isoforms by Mtb drives the host immune response towards a phenotype that facilitates the pathogen's survival.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:26 |
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| Enthalten in: |
Microbes and infection - 26(2024), 3 vom: 22. März, Seite 105282 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Roy, Trisha [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.03.2024 Date Revised 20.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.micinf.2023.105282 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM366256890 |
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| 520 | |a Mycobacterium tuberculosis (Mtb) infection leads to upregulation of Suppressors of Cytokine signaling (SOCS) expression in host macrophages (Mϕ). SOCS proteins inhibit cytokine signaling by negatively regulating JAK/STAT. We investigated this host-pathogen dialectic at the level of transcription. We used phorbol-differentiated THP-1 Mϕ infected with Mtb to investigate preferential upregulation of some SOCS isoforms that are known to inhibit signaling by IFN-γ, IL-12, and IL-6. We examined time kinetics of likely transcription factors and signaling molecules upstream of SOCS transcription, and survival of intracellular Mtb following SOCS upregulation. Our results suggest a plausible mechanism that involves PGE2 secretion during infection to induce the PKA/CREB axis, culminating in nuclear translocation of C/EBPβ to induce expression of SOCS1. Mtb-infected Mϕ secreted IL-10, suggesting a mechanism of induction of STAT3, which may subsequently induce SOCS3. We provide evidence of temporal variation in SOCS isoform exspression and decay. Small-interfering RNA-mediated knockdown of SOCS1 and SOCS3 restored the pro-inflammatory milieu and reduced Mtb viability. In mice infected with Mtb, SOCS isoforms persisted across Days 28-85 post infection. Our results suggest that differential temporal regulation of SOCS isoforms by Mtb drives the host immune response towards a phenotype that facilitates the pathogen's survival | ||
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| 700 | 1 | |a Shafi, Hasham |e verfasserin |4 aut | |
| 700 | 1 | |a Reddy, D V Siva |e verfasserin |4 aut | |
| 700 | 1 | |a Raman, Sunil Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Chakradhar, J V U S |e verfasserin |4 aut | |
| 700 | 1 | |a Verma, Sonia |e verfasserin |4 aut | |
| 700 | 1 | |a Bharti, Reena |e verfasserin |4 aut | |
| 700 | 1 | |a Azmi, Lubna |e verfasserin |4 aut | |
| 700 | 1 | |a Ray, Lipika |e verfasserin |4 aut | |
| 700 | 1 | |a Misra, Amit |e verfasserin |4 aut | |
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