title: Selective suppression of endothelial cytokine production by progesterone receptor.
abstract: Steroid hormones are well-recognized suppressors of the inflammatory response, however, their cell- and tissue-specific effects in the regulation of inflammation are far less understood, particularly for the sex-related steroids. To determine the contribution of progesterone in the endothelium, we have characterized and validated an in vitro culture system in which human umbilical vein endothelial cells constitutively express human progesterone receptor (PR). Using next generation RNA-sequencing, we identified a selective group of cytokines that are suppressed by progesterone both under physiological conditions and during pathological activation by lipopolysaccharide. In particular, IL-6, IL-8, CXCL2/3, and CXCL1 were found to be direct targets of PR, as determined by ChIP-sequencing. Regulation of these cytokines by progesterone was also confirmed by bead-based multiplex cytokine assays and quantitative PCR. These findings provide a novel role for PR in the direct regulation of cytokine levels secreted by the endothelium. They also suggest that progesterone-PR signaling in the endothelium directly impacts leukocyte trafficking in PR-expressing tissues.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Goddard
authors.forename: Amy N
authors.initials: AN
authors.lastname: Ton
authors.forename: Tõnis
authors.initials: T
authors.lastname: Org
authors.forename: Hanna K A
authors.initials: HK
authors.lastname: Mikkola
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
mesh_terms: D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D019743:Chemokines, CXC; D015850:Interleukin-6; D016209:Interleukin-8; D011980:Receptors, Progesterone; D011374:Progesterone
keywords: 4′,6-diamidino-2-phenylindole; DAPI; HUVEC; Immune cell; Inflammation; LPS; PR; PRKO; Reproduction; Steroid hormone; hPR; human progesterone receptor; human umbilical vein endothelial cell; lipopolysaccharide; progesterone receptor; progesterone receptor knockout