title: Prostaglandins from Cytosolic Phospholipase A2α/Cyclooxygenase-1 Pathway and Mitogen-activated Protein Kinases Regulate Gene Expression in Candida albicans-infected Macrophages.
abstract: In Candida albicans-infected resident peritoneal macrophages, activation of group IVA cytosolic phospholipase A2(cPLA2α) by calcium- and mitogen-activated protein kinases triggers the rapid production of prostaglandins I2 and E2 through cyclooxygenase (COX)-1 and regulates gene expression by increasing cAMP. InC. albicans-infected cPLA2α(-/-)or COX-1(-/-)macrophages, expression ofI l10,Nr4a2, and Ptgs2 was lower, and expression ofTnfα was higher, than in wild type macrophages. Expression was reconstituted with 8-bromo-cAMP, the PKA activator 6-benzoyl-cAMP, and agonists for prostaglandin receptors IP, EP2, and EP4 in infected but not uninfected cPLA2α(-/-)or COX-1(-/-)macrophages. InC. albicans-infected cPLA2α(+/+)macrophages, COX-2 expression was blocked by IP, EP2, and EP4 receptor antagonists, indicating a role for both prostaglandin I2 and E2 Activation of ERKs and p38, but not JNKs, by C. albicansacted synergistically with prostaglandins to induce expression of Il10,Nr4a2, and Ptgs2. Tnfα expression required activation of ERKs and p38 but was suppressed by cAMP. Results using cAMP analogues that activate PKA or Epacs suggested that cAMP regulates gene expression through PKA. However, phosphorylation of cAMP-response element-binding protein (CREB), the cAMP-regulated transcription factor involved inIl10,Nr4a2,Ptgs2, andTnfα expression, was not mediated by cAMP/PKA because it was similar inC. albicans-infected wild type and cPLA2α(-/-)or COX-1(-/-)macrophages. CREB phosphorylation was blocked by p38 inhibitors and induced by the p38 activator anisomycin but not by the PKA activator 6-benzoyl-cAMP. Therefore, MAPK activation inC. albicans-infected macrophages plays a dual role by promoting the cPLA2α/prostaglandin/cAMP/PKA pathway and CREB phosphorylation that coordinately regulate immediate early gene expression.
authors: From the Department of Pediatrics, National Jewish Health, Denver, Colorado 80206 and.
authors: Bogeon
authors: B
authors: Yun
authors: From the Department of Pediatrics, National Jewish Health, Denver, Colorado 80206 and.
authors: HeeJung
authors: H
authors: Lee
authors: From the Department of Pediatrics, National Jewish Health, Denver, Colorado 80206 and.
authors: Sabarirajan
authors: S
authors: Jayaraja
authors: From the Department of Pediatrics, National Jewish Health, Denver, Colorado 80206 and.
authors: Saritha
authors: S
authors: Suram
authors: the Departments of Pharmacology and.
authors: Robert C
authors: RC
authors: Murphy
authors: From the Department of Pediatrics, National Jewish Health, Denver, Colorado 80206 and the Departments of Pharmacology and Pathology, University of Colorado Denver, Aurora, Colorado 80045 lesliec@njhealth.org.
authors: Christina C
authors: CC
authors: Leslie
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002176:Candida albicans / Q000502:physiology*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000276:immunology; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology; D015232:Dinoprostone / Q000096:biosynthesis; D011464:Epoprostenol / Q000096:biosynthesis; D005786:Gene Expression Regulation; D054513:Group IV Phospholipases A2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C556062:IL10 protein, mouse; D008565:Membrane Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D047428:Protein Kinase Inhibitors; D011982:Receptors, Prostaglandin; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015124:8-Bromo Cyclic Adenosine Monophosphate; C050086:N(6)-benzoyl-cyclic AMP; D011464:Epoprostenol; D000242:Cyclic AMP; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D054513:Group IV Phospholipases A2; D015232:Dinoprostone
keywords: Candida albicans; c-Jun N-terminal kinase (JNK); cAMP-response element-binding protein (CREB); cyclic AMP (cAMP); extracellular signal-regulated kinase (ERK); mitogen-activated protein kinase (MAPK); p38 MAPK; phospholipase A; prostaglandin