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IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages.

Publication ,  Journal Article
Stanfield, BA; Purves, T; Palmer, S; Sullenger, B; Welty-Wolf, K; Haines, K; Agarwal, S; Kasotakis, G
Published in: PLoS One
2021

INTRODUCTION: Anti-inflammatory cytokine IL-10 suppresses pro-inflammatory IL-12b expression after Lipopolysaccharide (LPS) stimulation in colonic macrophages, as part of the innate immunity Toll-Like Receptor (TLR)-NF-κB activation system. This homeostatic mechanism limits excess inflammation in the intestinal mucosa, as it constantly interacts with the gut flora. This effect is reversed with Histone Deacetylase 3 (HDAC3), a class I HDAC, siRNA, suggesting it is mediated through HDAC3. Given alveolar macrophages' prominent role in Acute Lung Injury (ALI), we aim to determine whether a similar regulatory mechanism exists in the typically sterile pulmonary microenvironment. METHODS: Levels of mRNA and protein for IL-10, and IL-12b were determined by qPCR and ELISA/Western Blot respectively in naïve and LPS-stimulated alveolar macrophages. Expression of the NF-κB intermediaries was also similarly assessed. Experiments were repeated with AS101 (an IL-10 protein synthesis inhibitor), MS-275 (a selective class 1 HDAC inhibitor), or both. RESULTS: LPS stimulation upregulated all proinflammatory mediators assayed in this study. In the presence of LPS, inhibition of IL-10 and/or class 1 HDACs resulted in both synergistic and independent effects on these signaling molecules. Quantitative reverse-transcriptase PCR on key components of the TLR4 signaling cascade demonstrated significant diversity in IL-10 and related gene expression in the presence of LPS. Inhibition of IL-10 secretion and/or class 1 HDACs in the presence of LPS independently affected the transcription of MyD88, IRAK1, Rela and the NF-κB p50 subunit. Interestingly, by quantitative ELISA inhibition of IL-10 secretion and/or class 1 HDACs in the presence of LPS independently affected the secretion of not only IL-10, IL-12b, and TNFα, but also proinflammatory mediators CXCL2, IL-6, and MIF. These results suggest that IL-10 and class 1 HDAC activity regulate both independent and synergistic mechanisms of proinflammatory cytokine/chemokine signaling. CONCLUSIONS: Alveolar macrophages after inflammatory stimulation upregulate both IL-10 and IL-12b production, in a highly class 1 HDAC-dependent manner. Class 1 HDACs appear to help maintain the balance between the pro- and anti-inflammatory IL-12b and IL-10 respectively. Class 1 HDACs may be considered as targets for the macrophage-initiated pulmonary inflammation in ALI in a preclinical setting.

Duke Scholars

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2021

Volume

16

Issue

1

Start / End Page

e0245169

Location

United States

Related Subject Headings

  • Mice
  • Macrophages, Alveolar
  • Interleukin-12 Subunit p40
  • Interleukin-10
  • Inflammation Mediators
  • Histone Deacetylases
  • General Science & Technology
  • Cell Line
  • Animals
  • Acute Lung Injury
 

Citation

APA
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ICMJE
MLA
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Stanfield, B. A., Purves, T., Palmer, S., Sullenger, B., Welty-Wolf, K., Haines, K., … Kasotakis, G. (2021). IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages. PLoS One, 16(1), e0245169. https://doi.org/10.1371/journal.pone.0245169
Stanfield, Brent A., Todd Purves, Scott Palmer, Bruce Sullenger, Karen Welty-Wolf, Krista Haines, Suresh Agarwal, and George Kasotakis. “IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages.PLoS One 16, no. 1 (2021): e0245169. https://doi.org/10.1371/journal.pone.0245169.
Stanfield BA, Purves T, Palmer S, Sullenger B, Welty-Wolf K, Haines K, et al. IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages. PLoS One. 2021;16(1):e0245169.
Stanfield, Brent A., et al. “IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages.PLoS One, vol. 16, no. 1, 2021, p. e0245169. Pubmed, doi:10.1371/journal.pone.0245169.
Stanfield BA, Purves T, Palmer S, Sullenger B, Welty-Wolf K, Haines K, Agarwal S, Kasotakis G. IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages. PLoS One. 2021;16(1):e0245169.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2021

Volume

16

Issue

1

Start / End Page

e0245169

Location

United States

Related Subject Headings

  • Mice
  • Macrophages, Alveolar
  • Interleukin-12 Subunit p40
  • Interleukin-10
  • Inflammation Mediators
  • Histone Deacetylases
  • General Science & Technology
  • Cell Line
  • Animals
  • Acute Lung Injury