ORMDL3 overexpression facilitates FcεRI‐mediated transcription of proinflammatory cytokines and thapsigargin‐mediated PERK phosphorylation in RBL‐2H3 cells

Abstract Introduction The chromosomal region 17q21 harbors the human orosomucoid‐like 3 (ORMDL3) gene and has been linked to asthma and other inflammatory diseases. ORMDL3 is involved in the unfolded protein response (UPR), lipid metabolism, and inflammatory reactions. We investigated the effects of...

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Autores principales:	Kazuhiro Ogi, Tetsuji Takabayashi, Kaori Tomita, Masafumi Sakashita, Taiyo Morikawa, Takahiro Ninomiya, Masayuki Okamoto, Norihiko Narita, Shigeharu Fujieda
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	FTY720 mast cell ORMDL3 S1P UPR Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/f4a842e6381e47be82ec6d11a0cb3037
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spelling	oai:doaj.org-article:f4a842e6381e47be82ec6d11a0cb30372021-11-12T19:57:14ZORMDL3 overexpression facilitates FcεRI‐mediated transcription of proinflammatory cytokines and thapsigargin‐mediated PERK phosphorylation in RBL‐2H3 cells2050-452710.1002/iid3.489https://doaj.org/article/f4a842e6381e47be82ec6d11a0cb30372021-12-01T00:00:00Zhttps://doi.org/10.1002/iid3.489https://doaj.org/toc/2050-4527Abstract Introduction The chromosomal region 17q21 harbors the human orosomucoid‐like 3 (ORMDL3) gene and has been linked to asthma and other inflammatory diseases. ORMDL3 is involved in the unfolded protein response (UPR), lipid metabolism, and inflammatory reactions. We investigated the effects of ORMDL3 overexpression in RBL‐2H3 cells to determine the contribution of ORMDL3 to inflammatory disease development. Methods We generated ORMDL3 stably overexpressing RBL‐2H3 cells to assess degranulation, transcriptional upregulation of interleukin‐4 (IL‐4), tumor necrosis factor‐α (TNF‐α), monocyte chemoattractant protein‐1 (MCP‐1), and mitogen‐activated protein kinase (MAPK) phosphorylation via FcεRI. In addition, we examined the effects of ORMDL3 overexpression on thapsigargin (TG)‐mediated proinflammatory cytokine transcription and UPR by monitoring MAPK, protein kinase‐like endoplasmic reticulum kinase (PERK), and inositol‐requiring enzyme 1 (IRE1) phosphorylation. Results Overexpression of ORMDL3 enhanced IL‐4, TNF‐α, and MCP‐1 expression after FcεRI cross‐linking, whereas the sphingosine‐1‐phosphate (S1P) agonist FTY720 suppressed this enhancement. There was no significant difference in degranulation and MAPK phosphorylation via FcεRI‐mediated activation between vector‐transfected and ORMDL3‐overexpressing cells. ORMDL3 overexpression accelerated TG‐mediated PERK phosphorylation, while MAPK phosphorylation and proinflammatory cytokine expression showed no significant changes in ORMDL3‐overexpressing cells. Conclusions Our findings suggest that ORMDL3 plays an important role in regulating proinflammatory cytokine expression via the S1P pathway and selectively affects the UPR pathway in mast cells.Kazuhiro OgiTetsuji TakabayashiKaori TomitaMasafumi SakashitaTaiyo MorikawaTakahiro NinomiyaMasayuki OkamotoNorihiko NaritaShigeharu FujiedaWileyarticleFTY720mast cellORMDL3S1PUPRImmunologic diseases. AllergyRC581-607ENImmunity, Inflammation and Disease, Vol 9, Iss 4, Pp 1394-1405 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	FTY720 mast cell ORMDL3 S1P UPR Immunologic diseases. Allergy RC581-607
spellingShingle	FTY720 mast cell ORMDL3 S1P UPR Immunologic diseases. Allergy RC581-607 Kazuhiro Ogi Tetsuji Takabayashi Kaori Tomita Masafumi Sakashita Taiyo Morikawa Takahiro Ninomiya Masayuki Okamoto Norihiko Narita Shigeharu Fujieda ORMDL3 overexpression facilitates FcεRI‐mediated transcription of proinflammatory cytokines and thapsigargin‐mediated PERK phosphorylation in RBL‐2H3 cells
description	Abstract Introduction The chromosomal region 17q21 harbors the human orosomucoid‐like 3 (ORMDL3) gene and has been linked to asthma and other inflammatory diseases. ORMDL3 is involved in the unfolded protein response (UPR), lipid metabolism, and inflammatory reactions. We investigated the effects of ORMDL3 overexpression in RBL‐2H3 cells to determine the contribution of ORMDL3 to inflammatory disease development. Methods We generated ORMDL3 stably overexpressing RBL‐2H3 cells to assess degranulation, transcriptional upregulation of interleukin‐4 (IL‐4), tumor necrosis factor‐α (TNF‐α), monocyte chemoattractant protein‐1 (MCP‐1), and mitogen‐activated protein kinase (MAPK) phosphorylation via FcεRI. In addition, we examined the effects of ORMDL3 overexpression on thapsigargin (TG)‐mediated proinflammatory cytokine transcription and UPR by monitoring MAPK, protein kinase‐like endoplasmic reticulum kinase (PERK), and inositol‐requiring enzyme 1 (IRE1) phosphorylation. Results Overexpression of ORMDL3 enhanced IL‐4, TNF‐α, and MCP‐1 expression after FcεRI cross‐linking, whereas the sphingosine‐1‐phosphate (S1P) agonist FTY720 suppressed this enhancement. There was no significant difference in degranulation and MAPK phosphorylation via FcεRI‐mediated activation between vector‐transfected and ORMDL3‐overexpressing cells. ORMDL3 overexpression accelerated TG‐mediated PERK phosphorylation, while MAPK phosphorylation and proinflammatory cytokine expression showed no significant changes in ORMDL3‐overexpressing cells. Conclusions Our findings suggest that ORMDL3 plays an important role in regulating proinflammatory cytokine expression via the S1P pathway and selectively affects the UPR pathway in mast cells.
format	article
author	Kazuhiro Ogi Tetsuji Takabayashi Kaori Tomita Masafumi Sakashita Taiyo Morikawa Takahiro Ninomiya Masayuki Okamoto Norihiko Narita Shigeharu Fujieda
author_facet	Kazuhiro Ogi Tetsuji Takabayashi Kaori Tomita Masafumi Sakashita Taiyo Morikawa Takahiro Ninomiya Masayuki Okamoto Norihiko Narita Shigeharu Fujieda
author_sort	Kazuhiro Ogi
title	ORMDL3 overexpression facilitates FcεRI‐mediated transcription of proinflammatory cytokines and thapsigargin‐mediated PERK phosphorylation in RBL‐2H3 cells
title_short	ORMDL3 overexpression facilitates FcεRI‐mediated transcription of proinflammatory cytokines and thapsigargin‐mediated PERK phosphorylation in RBL‐2H3 cells
title_full	ORMDL3 overexpression facilitates FcεRI‐mediated transcription of proinflammatory cytokines and thapsigargin‐mediated PERK phosphorylation in RBL‐2H3 cells
title_fullStr	ORMDL3 overexpression facilitates FcεRI‐mediated transcription of proinflammatory cytokines and thapsigargin‐mediated PERK phosphorylation in RBL‐2H3 cells
title_full_unstemmed	ORMDL3 overexpression facilitates FcεRI‐mediated transcription of proinflammatory cytokines and thapsigargin‐mediated PERK phosphorylation in RBL‐2H3 cells
title_sort	ormdl3 overexpression facilitates fcεri‐mediated transcription of proinflammatory cytokines and thapsigargin‐mediated perk phosphorylation in rbl‐2h3 cells
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/f4a842e6381e47be82ec6d11a0cb3037
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ORMDL3 overexpression facilitates FcεRI‐mediated transcription of proinflammatory cytokines and thapsigargin‐mediated PERK phosphorylation in RBL‐2H3 cells

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