title: Janus kinase 3 activity is necessary for phosphorylation of cytosolic phospholipase A2 and prostaglandin E2 synthesis by macrophages infected with Francisella tularensis live vaccine strain.
abstract: Francisella tularensis, the causative agent of tularemia, modulates the host immune response to gain a survival advantage within the host. One mechanism of immune evasion is the ability of F. tularensis to induce the synthesis of the small lipid mediator prostaglandin E2 (PGE2), which alters the host T cell response making the host more susceptible to Francisella growth. PGE2 is synthesized by a tightly regulated biosynthetic pathway following stimulation. The synthesis of PGE2 begins with the liberation of arachidonic acid (AA) from membrane phospholipids by cytosolic phospholipase A2 (cPLA2). AA is subsequently converted to the unstable intermediate PGH2 by cyclooxygenase-2 (COX-2), and PGH2 undergoes an isomerization reaction to generate PGE2. Our objective was to identify F. tularensis-activated host signaling pathways that regulate the activity of the enzymes in the PGE2-biosynthetic pathway. In this study, we show that cPLA2, p38 mitogen-activated protein kinase (MAPK), and Janus kinase 3 (JAK3) signaling are necessary for F. tularensis-induced PGE2 production. Inhibition of JAK3 activity reduced the phosphorylation of cPLA2 and COX-2 protein levels. In addition, JAK3 regulates cPLA2 phosphorylation independent of transcription. Moreover, p38 MAPK activity is required for F. tularensis-induced COX-2 protein synthesis, but not for the phosphorylation of cPLA2. This research highlights a unique signaling axis in which JAK3 and p38 MAPK regulate the activity of multiple enzymes of the PGE2-biosynthetic pathway in macrophages infected with F. tularensis.
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, Louisiana, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Brummett
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Navratil
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Bryan
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Woolard
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism / Q000382:microbiology; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005604:Francisella tularensis / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D054510:Phospholipases A2, Cytosolic / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D014406:Tularemia / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016718:Arachidonic Acid; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D054510:Phospholipases A2, Cytosolic; D015232:Dinoprostone