Cytosolic phospholipase A2α enhances mouse mortality induced by Pseudomonas aeruginosa pulmonary infection via interleukin 6

Pseudomonas aeruginosa pulmonary infection is a leading cause of death in numerous diseases such as cystic fibrosis (CF). The host cytosolic phospholipase A2 alpha (cPLA2 alpha) releases lipid mediators that play an important role in the pathogenesis of diseases, but its role in lung injury induced by P. aeruginosa infection is still obscure. Using an animal model of P. aeruginosa lung infection, we showed that the CHA strain of P. aeruginosa was more potent than the PAK strain in inducing mouse mortality and lung injury, and that both mouse mortality and lung injury were reduced in cPLA2 alpha(-/-) mice as compared to cPLA2 alpha(+/+) mice. This was accompanied by decreased levels of IL6 but not other inflammatory cytokines (IL1 beta, KC and TNF alpha) in the bronchoalveolar lavage fluids (BALFs) of cPLA2 alpha(-/-) mice. Given that CFTR-/- mice exhibit increased cPLA2 alpha activation in the lung, the role of cPLA2 alpha was further examined in this lung infection model. Compared to littermates, P. aeruginosa infection caused increased mortality in CFTR-/- mice with high IL6 levels in BALFs, which was attenuated by pharmacological inhibition of cPLA2 alpha. In addition, compared to IL6(-/-) mice, an enhanced mortality was also observed in P. aeruginosa infected IL6(+/+) mice. Since alveolar macrophages (AMs) are the primary inflammatory cytokine source in the lung, murine AMs cell line (MH-S) were used to investigate the signalling pathways involved in this process. Incubation of MH-S cells with P. aeruginosa induced IL6 production, which was mediated by MAPKs ERK/p38 and was abolished by cPLA2 alpha inhibitors. Furthermore, among cPLA2 downstream signalling pathways, only 15-lipoxygenase (15-LOX) and cyclooxygenase-2 (COX-2) were proven to participate in this P. aeruginosa-induced IL6 expression. Based on all these observations, we conclude that cPLA2 alpha enhances P. aeruginosa-induced animal lethality in part via IL6 induction and that MAPKs ERK/p38, 15-LOX and COX-2 signalling pathways were involved in this process. (C) 2014 Elsevier B.V. and Societe francaise de biochimie et biologie Moleculaire (SFBBM). All rights reserved.