title: Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells.
abstract: Dendritic cell (DC) homeostasis, like all mature blood cells, is maintained via hierarchal generation from hematopoietic precursors; however, little is known about the regulatory mechanisms governing DC generation. Here, we show that prostaglandin E(2) (PGE(2)) is required for optimal Flt3 ligand-mediated DC development and regulates expression of the Flt3 receptor on DC-committed progenitor cells. Inhibition of PGE(2) biosynthesis reduces Flt3-mediated activation of STAT3 and expression of the antiapoptotic protein survivin, resulting in increased apoptosis of DC-committed progenitor cells. Reduced DC development caused by diminished PGE(2) signaling is reversed by overexpression of Flt3 or survivin in DC progenitors and conversely is mimicked by STAT3 inhibition. PGE(2) regulation of DC generation is specifically mediated through the EP1 and EP3 G protein PGE(2) receptors. These studies define a novel DC progenitor regulatory pathway in which PGE(2) signaling through EP1/EP3 receptors regulates Flt3 expression and downstream STAT3 activation and survivin expression, required for optimal DC progenitor survival and DC development in vivo.
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Pratibha
authors: P
authors: Singh
authors: Jonathan
authors: J
authors: Hoggatt
authors: Peirong
authors: P
authors: Hu
authors: Jennifer M
authors: JM
authors: Speth
authors: Seiji
authors: S
authors: Fukuda
authors: Richard M
authors: RM
authors: Breyer
authors: Louis M
authors: LM
authors: Pelus
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D007231:Infant, Newborn; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D006727:Hormone Antagonists; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D050796:STAT3 Transcription Factor; D000077022:Survivin; C084881:flt3 ligand protein; D015232:Dinoprostone