title: 17-oxo-DHA displays additive anti-inflammatory effects with fluticasone propionate and inhibits the NLRP3 inflammasome.
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.
authors.affiliation: Fondazione Ri.MED, via Bandiera 11, 90133 Palermo, Italy.|Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Via Ugo La Malfa 153, 90146 Palermo, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cipollina
authors.affiliation: Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Via Ugo La Malfa 153, 90146 Palermo, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Di Vincenzo
authors.affiliation: Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Via Ugo La Malfa 153, 90146 Palermo, Italy.
authors.forename: Liboria
authors.initials: L
authors.lastname: Siena
authors.affiliation: Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Via Ugo La Malfa 153, 90146 Palermo, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Di Sano
authors.affiliation: Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Via Ugo La Malfa 153, 90146 Palermo, Italy.
authors.forename: Mark
authors.initials: M
authors.lastname: Gjomarkaj
authors.affiliation: Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Via Ugo La Malfa 153, 90146 Palermo, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pace
mesh_terms: D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D016022:Case-Control Studies; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D002469:Cell Separation; D004281:Docosahexaenoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D000068298:Fluticasone / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009550:Nigericin / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D004281:Docosahexaenoic Acids; D000068298:Fluticasone; D020170:Caspase 1; D013755:Tetradecanoylphorbol Acetate; D009550:Nigericin