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

Abstract

Hematopoietic stem cell transplant (HSCT) treats or cures a variety of hematological and inherited disorders. Unfortunately, patients that 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 overexpression of prostaglandin E2 (PGE2) post-BMT signals via EP2 or EP4 to induce cyclic adenosine monophosphate (cAMP) which activates protein kinase A (PKA) or the exchange protein activated by cAMP (Epac) to induce cAMP response element binding (CREB)-dependent transcription of IL-1β leading to exacerbated lung injury in BMT mice. Induction of IL-1β by PGE2 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, PGE2 can limit autophagy-mediated killing of P. aeruginosa in alveolar macrophages, yet, autophagy doesn't play a role in PGE2-mediated up-regulation of IL-1β. Reducing PGE2 levels with indomethacin improved bacterial clearance and reduced IL-1β-mediated acute lung injury (ALI) in P. aeruginosa-infected BMT mice.