Oncotarget

Research Papers:

Inhibition of lysophosphatidic acid receptor ameliorates Sjögren’s syndrome in NOD mice

Eunhye Park, Donghee Kim, Song Mi Lee and Hee-Sook Jun _

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Oncotarget. 2017; 8:27240-27251. https://doi.org/10.18632/oncotarget.15916

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Abstract

Eunhye Park1,*, Donghee Kim1,*, Song Mi Lee1,2, Hee-Sook Jun1,2,3

1Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea

2College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, Republic of Korea

3Gil Medical Research Institute, Gil Hospital, Incheon, Republic of Korea

*These authors have contributed equally to this work

Correspondence to:

Hee-Sook Jun, email: hsjun@gachon.ac.kr

Keywords: Sjögren’s syndrome, LPA, Ki16425, NOD mice, IL-17

Received: June 11, 2016     Accepted: February 20, 2017     Published: March 06, 2017

ABSTRACT

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.


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