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Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice
Lysophosphatidic acid (LPA), a bioactive lysophospholipid, is involved in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study, we investigated the role of LPA/LPA receptor (LPAR) signaling in the pathogenesis of Sjögren's syndrome (SS). We found that autotaxin, an LP...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432331/ https://www.ncbi.nlm.nih.gov/pubmed/28460477 http://dx.doi.org/10.18632/oncotarget.15916 |
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author | Park, Eunhye Kim, Donghee Lee, Song Mi Jun, Hee-Sook |
author_facet | Park, Eunhye Kim, Donghee Lee, Song Mi Jun, Hee-Sook |
author_sort | Park, Eunhye |
collection | PubMed |
description | Lysophosphatidic acid (LPA), a bioactive lysophospholipid, is involved in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study, we investigated the role of LPA/LPA receptor (LPAR) signaling in the pathogenesis of Sjögren's syndrome (SS). We found that autotaxin, an LPA producing enzyme, and LPAR1 and LPAR3 mRNA, and IL-17 mRNA were highly expressed in the exocrine glands of 20-week-old nonobese diabetic (NOD) mice, which show SS symptoms at this age, as compared with non-symptomatic 8-week-old NOD mice. In an adoptive transfer model using NOD lymphocytes, treatment with Ki16425, an LPAR1/3 antagonist, restored tear and saliva secretion and decreased symptoms of SS compared with the vehicle-treated group. IL-17 levels in serum and lacrimal glands were also significantly reduced by Ki16425 in recipient mice. In addition, Ki16425 treatment of 20-week-old NOD mice, which spontaneously developed SS, restored saliva volume. Treatment of NOD splenocytes with LPA induced the expression of IL-17 in a dose-dependent manner, and Ki16425 inhibited this increase. LPA stimulated the activation of ROCK2 and p38 MAPK; and inhibition of ROCK2 or p38 MAPK suppressed LPA-induced IL-17 expression. Our data suggest that LPAR signaling stimulates SS development by induction of IL-17 production via ROCK and p38 MAPK pathways. Thus, LPAR inhibition could be a possible therapeutic strategy for SS. |
format | Online Article Text |
id | pubmed-5432331 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-54323312017-05-17 Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice Park, Eunhye Kim, Donghee Lee, Song Mi Jun, Hee-Sook Oncotarget Research Paper Lysophosphatidic acid (LPA), a bioactive lysophospholipid, is involved in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study, we investigated the role of LPA/LPA receptor (LPAR) signaling in the pathogenesis of Sjögren's syndrome (SS). We found that autotaxin, an LPA producing enzyme, and LPAR1 and LPAR3 mRNA, and IL-17 mRNA were highly expressed in the exocrine glands of 20-week-old nonobese diabetic (NOD) mice, which show SS symptoms at this age, as compared with non-symptomatic 8-week-old NOD mice. In an adoptive transfer model using NOD lymphocytes, treatment with Ki16425, an LPAR1/3 antagonist, restored tear and saliva secretion and decreased symptoms of SS compared with the vehicle-treated group. IL-17 levels in serum and lacrimal glands were also significantly reduced by Ki16425 in recipient mice. In addition, Ki16425 treatment of 20-week-old NOD mice, which spontaneously developed SS, restored saliva volume. Treatment of NOD splenocytes with LPA induced the expression of IL-17 in a dose-dependent manner, and Ki16425 inhibited this increase. LPA stimulated the activation of ROCK2 and p38 MAPK; and inhibition of ROCK2 or p38 MAPK suppressed LPA-induced IL-17 expression. Our data suggest that LPAR signaling stimulates SS development by induction of IL-17 production via ROCK and p38 MAPK pathways. Thus, LPAR inhibition could be a possible therapeutic strategy for SS. Impact Journals LLC 2017-03-06 /pmc/articles/PMC5432331/ /pubmed/28460477 http://dx.doi.org/10.18632/oncotarget.15916 Text en Copyright: © 2017 Park et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Park, Eunhye Kim, Donghee Lee, Song Mi Jun, Hee-Sook Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice |
title | Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice |
title_full | Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice |
title_fullStr | Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice |
title_full_unstemmed | Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice |
title_short | Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice |
title_sort | inhibition of lysophosphatidic acid receptor ameliorates sjögren's syndrome in nod mice |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432331/ https://www.ncbi.nlm.nih.gov/pubmed/28460477 http://dx.doi.org/10.18632/oncotarget.15916 |
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