| Autor: |
Martínez-Colón GJ; Immunology Graduate Program, University of Michigan, Ann Arbor, Michigan, USA., Taylor QM; Literature, Sciences and the Arts, Microbiology, University of Michigan, Ann Arbor, Michigan, USA., Wilke CA; Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA., Podsiad AB; Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA., Moore BB; Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA. |
| Abstrakt: |
Hematopoietic stem cell transplant (HSCT) treats or cures a variety of hematological and inherited disorders. Unfortunately, patients who undergo HSCT are susceptible to infections by a wide array of opportunistic pathogens. Pseudomonas aeruginosa bacteria can have life-threatening effects in HSCT patients by causing lung pathology that has been linked to high levels of the potent pro-inflammatory cytokine, interleukin-1β (IL-1β). Using a murine bone marrow transplant (BMT) model, we show that overexpression of prostaglandin E 2 (PGE 2 ) post-BMT signals via EP2 or EP4 to induce cyclic adenosine monophosphate (cAMP), which activates protein kinase A or the exchange protein activated by cAMP (Epac) to induce cAMP response element binding-dependent transcription of IL-1β leading to exacerbated lung injury in BMT mice. Induction of IL-1β by PGE 2 is time and dose dependent. Interestingly, IL-1β processing post-P. aeruginosa infection occurs via the enzymatic activity of either caspase-1 or caspase-8. Furthermore, PGE 2 can limit autophagy-mediated killing of P. aeruginosa in alveolar macrophages, yet autophagy does not have a role in PGE 2 -mediated upregulation of IL-1β. Reducing PGE 2 levels with indomethacin improved bacterial clearance and reduced IL-1β-mediated acute lung injury in P. aeruginosa-infected BMT mice. |
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