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Elevated prostaglandin E2 post-bone marrow transplant mediates interleukin-1?-related lung injury.


ABSTRACT: 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-1? (IL-1?). Using a murine bone marrow transplant (BMT) model, we show that overexpression of prostaglandin E2 (PGE2) 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-1? leading to exacerbated lung injury in BMT mice. Induction of IL-1? by PGE2 is time and dose dependent. Interestingly, IL-1? processing post-P. aeruginosa infection occurs via the enzymatic activity of either caspase-1 or caspase-8. Furthermore, PGE2 can limit autophagy-mediated killing of P. aeruginosa in alveolar macrophages, yet autophagy does not have a role in PGE2-mediated upregulation of IL-1?. Reducing PGE2 levels with indomethacin improved bacterial clearance and reduced IL-1?-mediated acute lung injury in P. aeruginosa-infected BMT mice.

SUBMITTER: Martinez-Colon GJ 

PROVIDER: S-EPMC5720939 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Elevated prostaglandin E<sub>2</sub> post-bone marrow transplant mediates interleukin-1β-related lung injury.

Martínez-Colón G J GJ   Taylor Q M QM   Wilke C A CA   Podsiad A B AB   Moore B B BB  

Mucosal immunology 20170607 2


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 o  ...[more]

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