IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages
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.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2021 |
---|---|
Erschienen: |
2021 |
Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
---|---|
Enthalten in: |
PloS one - 16(2021), 1 vom: 01., Seite e0245169 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Stanfield, Brent A [VerfasserIn] |
---|
Links: |
---|
Themen: |
130068-27-8 |
---|
Anmerkungen: |
Date Completed 10.05.2021 Date Revised 10.05.2021 published: Electronic-eCollection Citation Status MEDLINE |
---|
doi: |
10.1371/journal.pone.0245169 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM320341747 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM320341747 | ||
003 | DE-627 | ||
005 | 20231225173353.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231225s2021 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1371/journal.pone.0245169 |2 doi | |
028 | 5 | 2 | |a pubmed24n1067.xml |
035 | |a (DE-627)NLM320341747 | ||
035 | |a (NLM)33471802 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Stanfield, Brent A |e verfasserin |4 aut | |
245 | 1 | 0 | |a IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages |
264 | 1 | |c 2021 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 10.05.2021 | ||
500 | |a Date Revised 10.05.2021 | ||
500 | |a published: Electronic-eCollection | ||
500 | |a Citation Status MEDLINE | ||
520 | |a 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 | ||
520 | |a 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 | ||
520 | |a 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 | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 7 | |a IL10 protein, mouse |2 NLM | |
650 | 7 | |a Il12b protein, mouse |2 NLM | |
650 | 7 | |a Inflammation Mediators |2 NLM | |
650 | 7 | |a Interleukin-12 Subunit p40 |2 NLM | |
650 | 7 | |a Interleukin-10 |2 NLM | |
650 | 7 | |a 130068-27-8 |2 NLM | |
650 | 7 | |a Histone Deacetylases |2 NLM | |
650 | 7 | |a EC 3.5.1.98 |2 NLM | |
700 | 1 | |a Purves, Todd |e verfasserin |4 aut | |
700 | 1 | |a Palmer, Scott |e verfasserin |4 aut | |
700 | 1 | |a Sullenger, Bruce |e verfasserin |4 aut | |
700 | 1 | |a Welty-Wolf, Karen |e verfasserin |4 aut | |
700 | 1 | |a Haines, Krista |e verfasserin |4 aut | |
700 | 1 | |a Agarwal, Suresh |e verfasserin |4 aut | |
700 | 1 | |a Kasotakis, George |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t PloS one |d 2006 |g 16(2021), 1 vom: 01., Seite e0245169 |w (DE-627)NLM167327399 |x 1932-6203 |7 nnns |
773 | 1 | 8 | |g volume:16 |g year:2021 |g number:1 |g day:01 |g pages:e0245169 |
856 | 4 | 0 | |u http://dx.doi.org/10.1371/journal.pone.0245169 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 16 |j 2021 |e 1 |b 01 |h e0245169 |