title: Glycogen synthase kinase 3 activation is important for anthrax edema toxin-induced dendritic cell maturation and anthrax toxin receptor 2 expression in macrophages.
abstract: Anthrax edema toxin (ET) is one of two binary toxins produced by Bacillus anthracis that contributes to the virulence of this pathogen. ET is an adenylate cyclase that generates high levels of cyclic AMP (cAMP), causing alterations in multiple host cell signaling pathways. We previously demonstrated that ET increases cell surface expression of the anthrax toxin receptors (ANTXR) in monocyte-derived cells and promotes dendritic cell (DC) migration toward the lymph node-homing chemokine MIP-3β. In this work, we sought to determine if glycogen synthase kinase 3 (GSK-3) is important for ET-induced modulation of macrophage and DC function. We demonstrate that inhibition of GSK-3 dampens ET-induced maturation and migration processes of monocyte-derived dendritic cells (MDDCs). Additional studies reveal that the ET-induced expression of ANTXR in macrophages was decreased when GSK-3 activity was disrupted with chemical inhibitors or with small interfering RNA (siRNA) targeting GSK-3. Further examination of the ET induction of ANTXR revealed that a dominant negative form of CREB could block the ET induction of ANTXR, suggesting that CREB or a related family member was involved in the upregulation of ANTXR. Because CREB and GSK-3 activity appeared to be important for ET-induced ANTXR expression, the impact of GSK-3 on ET-induced CREB activity was examined in RAW 264.7 cells possessing a CRE-luciferase reporter. As with ANTXR expression, the ET induction of the CRE reporter was decreased by reducing GSK-3 activity. These studies not only provide insight into host pathways targeted by ET but also shed light on interactions between GSK-3 and CREB pathways in host immune cells.
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Larabee
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Maldonado-Arocho
authors.forename: Sergio
authors.initials: S
authors.lastname: Pacheco
authors.forename: Bryan
authors.initials: B
authors.lastname: France
authors.forename: Kevin
authors.initials: K
authors.lastname: DeGiusti
authors.forename: Salika M
authors.initials: SM
authors.lastname: Shakir
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Bradley
authors.forename: Jimmy D
authors.initials: JD
authors.lastname: Ballard
mesh_terms: D000818:Animals; D000881:Anthrax / Q000276:immunology* / Q000473:pathology*; D000942:Antigens, Bacterial / Q000633:toxicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018000:Receptors, Peptide / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D018000:Receptors, Peptide; C030325:anthrax toxin; C070309:anthrax toxin receptors; D038362:Glycogen Synthase Kinase 3