Ketoprofen Impairs Immunosuppression Induced by Severe Sepsis and Reveals an Important Role for Prostaglandin E2

Abstract

The mechanism of immunosuppression induced by severe sepsis is not fully understood. The production of prostaglandin E2 (PGE2) during sepsis is well known, but its role in long-term consequences of sepsis has not been explored. The current study evaluates the role of PGE2 in the development of immunosuppression secondary to sepsis and its potential as therapeutic target. Cecal ligation and puncture was used as an experimental model for sepsis induction in Balb/c and C57BL/6 mice. Immunosuppression was evaluated by the response to secondary infection with Aspergillus fumigatus in sepsis survivors. The role of prostanoids was evaluated in vivo and in vitro by treatment with the cyclooxygenase inhibitor ketoprofen. Balb/c mice were more susceptible than C57BL/6 to severe sepsis and to secondary infection, with a greater mortality rate. Prostaglandin E2 concentrations found in bronchoalveolar lavage in sham and cecal ligation and puncture group after fungal challenge were much higher in Balb/c than in C57BL/6 mice. Ketoprofen treatment improved survival of septic Balb/c mice subjected to secondary infection, while also enhancing macrophage phagocytosis and neutrophil recruitment to the lungs. We identified a pivotal role for PGE2 acting on EP4 receptors in modulating cytokine production differentially by sham and septic macrophages. Furthermore, sepsis also altered key enzymes in PGE2 synthesis and degradation. Our results indicate the involvement of PGE2 in severe sepsis-induced immunosuppression. Inhibition of PGE2 production represents an attractive target to improve innate immune response against secondary infection in the immunocompromised host.

Polarization of the Innate Immune Response by Prostaglandin E2: A Puzzle of Receptors and Signals

“…Studies addressing the role of PGE 2 in the development of immunosuppression secondary to sepsis in a model of cecal ligation and puncture complemented with secondary infection with Aspergillus fumigatus, disclosed that inhibition of COX was associated with improved survival to secondary infection. EP4 receptors were identified as the main type involved in modulating cytokine production (Brogliato et al, 2012). Altogether, these data indicate that the predominant function of PGE 2 in vivo consists of the downregulation of the phagocytic activity and the immune response.…”

Prostaglandin E2Reduces Toll-Like Receptor 4 Expression in Alveolar Macrophages by Inhibition of Translation

“…The ability of PGE 2 to down-regulate TLR4 could also potentially explain the phenomenon of LPS tolerance, in which prior exposure to LPS can cause reduced secretion of TNF-a in response to a subsequent challenge (34). Indeed, PGE 2 has been implicated in the phenomenon of immunoparalysis after sepsis (35), and down-regulation of TLR4 expression could contribute to this.…”

Induction of Cyclooxygenase-2 Signaling by Stomatococcus mucilaginosus Highlights the Pathogenic Potential of an Oral Commensal

“…COX-2-deficient mice display resistance against detrimental effects of endotoxemia (50,51). Modulation of immune response by COX-2 is largely related to an increased production of PGE 2 , which has been shown to be immunosuppressive in animal models of bacterial pneumonias and sepsis (21,23,(52)(53)(54). PGE 2 can also be produced by induction of mPGE synthases, depending on the stimulus (55,56).…”