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

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 beta (IL-1 beta). 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-1 beta leading to exacerbated lung injury in BMT mice. Induction of IL-1 beta by PGE(2) is time and dose dependent. Interestingly, IL-1 beta 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-1 beta. Reducing PGE2 levels with indomethacin improved bacterial clearance and reduced IL-1 beta-mediated acute lung injury in P. aeruginosa-infected BMT mice.