| First Author | Guillemot L | Year | 2014 |
| Journal | Biochimie | Volume | 107 Pt A |
| Pages | 95-104 | PubMed ID | 25201511 |
| Mgi Jnum | J:232461 | Mgi Id | MGI:5779272 |
| Doi | 10.1016/j.biochi.2014.08.018 | Citation | Guillemot L, et al. (2014) Cytosolic phospholipase A2alpha enhances mouse mortality induced by Pseudomonas aeruginosa pulmonary infection via interleukin 6. Biochimie 107 Pt A:95-104 |
| abstractText | Pseudomonas aeruginosa pulmonary infection is a leading cause of death in numerous diseases such as cystic fibrosis (CF). The host cytosolic phospholipase A2alpha (cPLA2alpha) 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 cPLA2alpha(-/-) mice as compared to cPLA2alpha(+/+) mice. This was accompanied by decreased levels of IL6 but not other inflammatory cytokines (IL1beta, KC and TNFalpha) in the bronchoalveolar lavage fluids (BALFs) of cPLA2alpha(-/-) mice. Given that CFTR(-/-) mice exhibit increased cPLA2alpha activation in the lung, the role of cPLA2alpha 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 cPLA2alpha. 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 cPLA2alpha 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 cPLA2alpha 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. |
