Limits...
17-oxo-DHA displays additive anti-inflammatory effects with fluticasone propionate and inhibits the NLRP3 inflammasome

View Article: PubMed Central - PubMed

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function associated with increased local and systemic inflammatory markers, such as TNFα and IL-1β. Glucocorticoids are used to treat this chronic disease, however their efficacy is low and new drugs are very much required. 17-oxo-DHA is a cyclooxygenase-2-dependent, electrophilic, α,β-unsaturated keto-derivative of docosahexaenoic acid with anti-inflammatory properties. We evaluated the action of 17-oxo-DHA alone or in combination with the steroid fluticasone propionate (FP) in peripheral blood mononuclear cells (PBMCs) from COPD patients and healthy individuals exposed to lipopolysaccharide. We show that PBMCs from COPD patients released higher levels of TNFα and IL-1β compared to controls. 17-oxo-DHA displayed strong anti-inflammatory effects. The addition of 17-oxo-DHA in combination with FP showed enhanced anti-inflammatory effects through the modulation of transcriptional and post-transcriptional mechanisms. 17-oxo-DHA, but not FP, was able to suppress the release of mature IL-1β through inhibition of the NLRP3 inflammasome. Furthermore, 17-oxo-DHA inhibited inflammasome-dependent degradation of the glucocorticoid receptor (GR). Our findings suggest that 17-oxo-DHA in combination with FP or other steroids might achieve higher therapeutic efficacy than steroids alone. Combined treatment might be particularly relevant in those conditions where increased inflammasome activation may lead to GR degradation and steroid-unresponsive inflammation.

No MeSH data available.


17-oxo-DHA, but not FP, inhibits inflammasome-dependent degradation of the glucocorticoid receptor.THP-1 cells were treated with PMA for 48 h then stimulated with 1 μg/ml LPS for 3.5 h, followed by FP (10 nM) or 17-oxo-DHA (10 μM) for 30 min, then by 10 μM nigericin for 30 min in serum-free medium. Expression of glucocorticoid receptor was measured in total cell lysates. Densitomeric analysis (N = 5) and a representative western blot image from five independent experiments are reported.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5121625&req=5

f9: 17-oxo-DHA, but not FP, inhibits inflammasome-dependent degradation of the glucocorticoid receptor.THP-1 cells were treated with PMA for 48 h then stimulated with 1 μg/ml LPS for 3.5 h, followed by FP (10 nM) or 17-oxo-DHA (10 μM) for 30 min, then by 10 μM nigericin for 30 min in serum-free medium. Expression of glucocorticoid receptor was measured in total cell lysates. Densitomeric analysis (N = 5) and a representative western blot image from five independent experiments are reported.

Mentions: Inspired by a recent article showing that steroid-resistance in leukemia cells is caused by caspase-1-dependent cleavage of the GR30, we hypothesized that the activation of the NLRP3 inflammasome in THP-1 cells could lead to a reduction of GR levels. Data reported in Fig. 9 show that nigericin-dependent activation of the NLRP3 inflammasome significantly reduces GR levels. Interestingly, 17-oxoDHA, but not FP, inhibited nigericin-dependent degradation of GR and restored the receptor levels back to baseline.


17-oxo-DHA displays additive anti-inflammatory effects with fluticasone propionate and inhibits the NLRP3 inflammasome
17-oxo-DHA, but not FP, inhibits inflammasome-dependent degradation of the glucocorticoid receptor.THP-1 cells were treated with PMA for 48 h then stimulated with 1 μg/ml LPS for 3.5 h, followed by FP (10 nM) or 17-oxo-DHA (10 μM) for 30 min, then by 10 μM nigericin for 30 min in serum-free medium. Expression of glucocorticoid receptor was measured in total cell lysates. Densitomeric analysis (N = 5) and a representative western blot image from five independent experiments are reported.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121625&req=5

f9: 17-oxo-DHA, but not FP, inhibits inflammasome-dependent degradation of the glucocorticoid receptor.THP-1 cells were treated with PMA for 48 h then stimulated with 1 μg/ml LPS for 3.5 h, followed by FP (10 nM) or 17-oxo-DHA (10 μM) for 30 min, then by 10 μM nigericin for 30 min in serum-free medium. Expression of glucocorticoid receptor was measured in total cell lysates. Densitomeric analysis (N = 5) and a representative western blot image from five independent experiments are reported.
Mentions: Inspired by a recent article showing that steroid-resistance in leukemia cells is caused by caspase-1-dependent cleavage of the GR30, we hypothesized that the activation of the NLRP3 inflammasome in THP-1 cells could lead to a reduction of GR levels. Data reported in Fig. 9 show that nigericin-dependent activation of the NLRP3 inflammasome significantly reduces GR levels. Interestingly, 17-oxoDHA, but not FP, inhibited nigericin-dependent degradation of GR and restored the receptor levels back to baseline.

View Article: PubMed Central - PubMed

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function associated with increased local and systemic inflammatory markers, such as TNFα and IL-1β. Glucocorticoids are used to treat this chronic disease, however their efficacy is low and new drugs are very much required. 17-oxo-DHA is a cyclooxygenase-2-dependent, electrophilic, α,β-unsaturated keto-derivative of docosahexaenoic acid with anti-inflammatory properties. We evaluated the action of 17-oxo-DHA alone or in combination with the steroid fluticasone propionate (FP) in peripheral blood mononuclear cells (PBMCs) from COPD patients and healthy individuals exposed to lipopolysaccharide. We show that PBMCs from COPD patients released higher levels of TNFα and IL-1β compared to controls. 17-oxo-DHA displayed strong anti-inflammatory effects. The addition of 17-oxo-DHA in combination with FP showed enhanced anti-inflammatory effects through the modulation of transcriptional and post-transcriptional mechanisms. 17-oxo-DHA, but not FP, was able to suppress the release of mature IL-1β through inhibition of the NLRP3 inflammasome. Furthermore, 17-oxo-DHA inhibited inflammasome-dependent degradation of the glucocorticoid receptor (GR). Our findings suggest that 17-oxo-DHA in combination with FP or other steroids might achieve higher therapeutic efficacy than steroids alone. Combined treatment might be particularly relevant in those conditions where increased inflammasome activation may lead to GR degradation and steroid-unresponsive inflammation.

No MeSH data available.