Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes†

Griffin, Sholeem; Healey, Gareth; Sheldon, I Martin; Sheldon, Martin

doi:10.1093/biolre/ioy099

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Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes†

Sholeem Griffin, Gareth Healey

, I Martin Sheldon, Martin Sheldon

Biology of Reproduction, Volume: 99, Issue: 4, Pages: 749 - 760

Swansea University Authors: Gareth Healey , Martin Sheldon

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DOI (Published version): 10.1093/biolre/ioy099

Abstract

Preventing postpartum uterine disease depends on the ability of endometrial cells to tolerate the presence of the bacteria that invade the uterus after parturition. Postpartum uterine disease and endometrial pathology in cattle is most associated with the pathogen Trueperella pyogenes. Trueperella p...

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Published in:	Biology of Reproduction
ISSN:	0006-3363 1529-7268
Published:	2018
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa39610
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first_indexed	2018-04-27T19:32:23Z
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spelling	2020-07-13T11:46:43.1118986 v2 39610 2018-04-27 Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes† 5926519f89187489cfd5e1478aa188b1 0000-0001-9531-1220 Gareth Healey Gareth Healey true false ab0f74b794e59cc270c69e63ee1d9748 0000-0001-7902-5558 Martin Sheldon Martin Sheldon true false 2018-04-27 PMSC Preventing postpartum uterine disease depends on the ability of endometrial cells to tolerate the presence of the bacteria that invade the uterus after parturition. Postpartum uterine disease and endometrial pathology in cattle is most associated with the pathogen Trueperella pyogenes. Trueperella pyogenes secretes a cholesterol-dependent cytolysin, pyolysin, which causes cytolysis by forming pores in the plasma membrane of endometrial stromal cells. The aim of the present study was to identify cell-intrinsic pathways that increase bovine endometrial stromal cell tolerance to pyolysin. Pyolysin caused dose-dependent cytolysis of bovine endometrial stromal cells and leakage of lactate dehydrogenase into supernatants. Cell tolerance to pyolysin was increased by inhibitors that target the mevalonate and cholesterol synthesis pathway, but not the mitogen-activated protein kinase, cell cycle, or metabolic pathways. Cellular cholesterol was reduced and cell tolerance to pyolysin was increased by supplying the mevalonate-derived isoprenoid farnesyl pyrophosphate, or by inhibiting farnesyl-diphosphate farnesyltransferase 1 or geranylgeranyl diphosphate synthase 1 to increase the abundance of farnesyl pyrophosphate. Supplying the mevalonate-derived isoprenoid geranylgeranyl pyrophosphate also increased cell tolerance to pyolysin, but independent of changes in cellular cholesterol. However, geranylgeranyl pyrophosphate inhibits nuclear receptor subfamily 1 group H receptors (NR1H, also known as Liver X receptors), and reducing the expression of the genes encoding NR1H3 or NR1H2 increased stromal cell tolerance to pyolysin. In conclusion, mevalonate-derived isoprenoids increased bovine endometrial stromal cell tolerance to pyolysin, which was associated with reducing cellular cholesterol and inhibiting NR1H receptors. Journal Article Biology of Reproduction 99 4 749 760 0006-3363 1529-7268 31 12 2018 2018-12-31 10.1093/biolre/ioy099 COLLEGE NANME Medicine COLLEGE CODE PMSC Swansea University BBSRC, BB/K006592/1 2020-07-13T11:46:43.1118986 2018-04-27T17:04:08.2353564 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Sholeem Griffin 1 Gareth Healey 0000-0001-9531-1220 2 I Martin Sheldon 3 Martin Sheldon 0000-0001-7902-5558 4 0039610-21092018151055.pdf APCE003.Sheldon.ioy099.pdf 2018-09-21T15:10:55.6570000 Output 1598964 application/pdf Version of Record true 2018-09-21T00:00:00.0000000 Distributed under the terms of a Creative Commons CC-BY 4.0 Licence. true eng
title	Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes†
spellingShingle	Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes† Gareth Healey Martin Sheldon
title_short	Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes†
title_full	Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes†
title_fullStr	Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes†
title_full_unstemmed	Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes†
title_sort	Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes†
author_id_str_mv	5926519f89187489cfd5e1478aa188b1 ab0f74b794e59cc270c69e63ee1d9748
author_id_fullname_str_mv	5926519f89187489cfd5e1478aa188b1_*_Gareth Healey ab0f74b794e59cc270c69e63ee1d9748_*_Martin Sheldon
author	Gareth Healey Martin Sheldon
author2	Sholeem Griffin Gareth Healey I Martin Sheldon Martin Sheldon
format	Journal article
container_title	Biology of Reproduction
container_volume	99
container_issue	4
container_start_page	749
publishDate	2018
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issn	0006-3363 1529-7268
doi_str_mv	10.1093/biolre/ioy099
college_str	Faculty of Medicine, Health and Life Sciences
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department_str	Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description	Preventing postpartum uterine disease depends on the ability of endometrial cells to tolerate the presence of the bacteria that invade the uterus after parturition. Postpartum uterine disease and endometrial pathology in cattle is most associated with the pathogen Trueperella pyogenes. Trueperella pyogenes secretes a cholesterol-dependent cytolysin, pyolysin, which causes cytolysis by forming pores in the plasma membrane of endometrial stromal cells. The aim of the present study was to identify cell-intrinsic pathways that increase bovine endometrial stromal cell tolerance to pyolysin. Pyolysin caused dose-dependent cytolysis of bovine endometrial stromal cells and leakage of lactate dehydrogenase into supernatants. Cell tolerance to pyolysin was increased by inhibitors that target the mevalonate and cholesterol synthesis pathway, but not the mitogen-activated protein kinase, cell cycle, or metabolic pathways. Cellular cholesterol was reduced and cell tolerance to pyolysin was increased by supplying the mevalonate-derived isoprenoid farnesyl pyrophosphate, or by inhibiting farnesyl-diphosphate farnesyltransferase 1 or geranylgeranyl diphosphate synthase 1 to increase the abundance of farnesyl pyrophosphate. Supplying the mevalonate-derived isoprenoid geranylgeranyl pyrophosphate also increased cell tolerance to pyolysin, but independent of changes in cellular cholesterol. However, geranylgeranyl pyrophosphate inhibits nuclear receptor subfamily 1 group H receptors (NR1H, also known as Liver X receptors), and reducing the expression of the genes encoding NR1H3 or NR1H2 increased stromal cell tolerance to pyolysin. In conclusion, mevalonate-derived isoprenoids increased bovine endometrial stromal cell tolerance to pyolysin, which was associated with reducing cellular cholesterol and inhibiting NR1H receptors.
published_date	2018-12-31T03:50:20Z
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Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes†

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