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Transcriptional regulation of suppressors of cytokine signaling during infection with Mycobacterium tuberculosis in human THP-1-derived macrophages and in mice. | LitMetric

AI Article Synopsis

  • Mycobacterium tuberculosis (Mtb) infection increases the expression of Suppressors of Cytokine Signaling (SOCS) proteins in macrophages, which negatively regulate immune signaling pathways.
  • The study used THP-1 macrophages infected with Mtb to explore how certain SOCS isoforms are upregulated and how this affects cytokine signaling, particularly noting the roles of various transcription factors and molecular signaling pathways.
  • Findings indicate that Mtb infection influences SOCS expression over time, promoting a favorable environment for the bacteria by dampening the host's inflammatory response, and reducing macrophage's ability to eliminate the pathogen.

Article Abstract

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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Source
http://dx.doi.org/10.1016/j.micinf.2023.105282DOI Listing

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