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 2signaling 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 PGE2 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.
ASJC Scopus subject areas
- Cell Biology