Calreticulin induced endothelial ICAM-1 up-regulation associated with tristetraprolin expression alteration through PI3K/Akt/eNOS/p38 MAPK signaling pathway in rheumatoid arthritis
Copyright © 2019 Elsevier Ltd. All rights reserved..
The present study was undertaken to determine whether extracellular calreticulin (CRT) participates in the regulation of ICAM-1in rheumatoid arthritis (RA) and further explore the potential mechanism. Our results showed that ICAM-1 and VCAM-1 levels were positively correlated with CRT levels in RA serum and synovial fluid, respectively. In RA synovial tissue, increased co-expressions of CRT and ICAM-1 in vascular endothelium and perivascular areas and elevated co-location of CRT and VCAM-1 localized predominantly to lining layer were observed compared to those in OA. In in vitro HUVECs model, enhanced ICAM-1expression and increased phosphorylation levels of Akt and eNOS were detected in the presence of CRT. Increased phosphorylated eNOS was significantly inhibited by a PI3K inhibitor LY294002 and elevated ICAM-1expression was partially blocked by the inhibitors of both PI3K and eNOS (L-NAME). It has been certified that the RNA-binding protein TTP targets AU-rich elements in the ICAM-1 3'-UTR and suppresses ICAM-1 expression. Knocking down TTP in HUVECs led to an increased induction of ICAM-1 by CRT. We have currently known that activation of p38 downstream kinase MK-2 leads to phosphorylation and inactivation of human TTP. The block of p38 MAPK/MK-2 signaling led to decreased protein expression and mRNA stability of TTP and ICAM-1. Furthermore, L-NAME and/or LY294002 pre-treated HUVECs manifested decreased p38 and MK-2 phosphorylation, which was accompanied by reduced TTP and ICAM-1 protein expression as well as decreased mRNA stability. Our results suggested that CRT could promote ICAM-1 expression in endothelial cells through PI3K/Akt/eNOS/p38 MAPK signaling mediated TTP accumulation, probably in an inactive form, which may provide a possible proinflammatory mechanism of CRT in RA.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:107 |
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| Enthalten in: |
Molecular immunology - 107(2019) vom: 02. März, Seite 10-20 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Yixin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.05.2019 Date Revised 03.05.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.molimm.2019.01.005 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 100 | 1 | |a Liu, Yixin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Calreticulin induced endothelial ICAM-1 up-regulation associated with tristetraprolin expression alteration through PI3K/Akt/eNOS/p38 MAPK signaling pathway in rheumatoid arthritis |
| 264 | 1 | |c 2019 | |
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| 500 | |a Date Revised 03.05.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 Elsevier Ltd. All rights reserved. | ||
| 520 | |a The present study was undertaken to determine whether extracellular calreticulin (CRT) participates in the regulation of ICAM-1in rheumatoid arthritis (RA) and further explore the potential mechanism. Our results showed that ICAM-1 and VCAM-1 levels were positively correlated with CRT levels in RA serum and synovial fluid, respectively. In RA synovial tissue, increased co-expressions of CRT and ICAM-1 in vascular endothelium and perivascular areas and elevated co-location of CRT and VCAM-1 localized predominantly to lining layer were observed compared to those in OA. In in vitro HUVECs model, enhanced ICAM-1expression and increased phosphorylation levels of Akt and eNOS were detected in the presence of CRT. Increased phosphorylated eNOS was significantly inhibited by a PI3K inhibitor LY294002 and elevated ICAM-1expression was partially blocked by the inhibitors of both PI3K and eNOS (L-NAME). It has been certified that the RNA-binding protein TTP targets AU-rich elements in the ICAM-1 3'-UTR and suppresses ICAM-1 expression. Knocking down TTP in HUVECs led to an increased induction of ICAM-1 by CRT. We have currently known that activation of p38 downstream kinase MK-2 leads to phosphorylation and inactivation of human TTP. The block of p38 MAPK/MK-2 signaling led to decreased protein expression and mRNA stability of TTP and ICAM-1. Furthermore, L-NAME and/or LY294002 pre-treated HUVECs manifested decreased p38 and MK-2 phosphorylation, which was accompanied by reduced TTP and ICAM-1 protein expression as well as decreased mRNA stability. Our results suggested that CRT could promote ICAM-1 expression in endothelial cells through PI3K/Akt/eNOS/p38 MAPK signaling mediated TTP accumulation, probably in an inactive form, which may provide a possible proinflammatory mechanism of CRT in RA | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Calreticulin | |
| 650 | 4 | |a Intercellular adhesion molecule-1 | |
| 650 | 4 | |a Rheumatoid arthritis | |
| 650 | 4 | |a Signaling pathway | |
| 650 | 4 | |a Tristetraprolin | |
| 650 | 7 | |a CALR protein, human |2 NLM | |
| 650 | 7 | |a Calreticulin |2 NLM | |
| 650 | 7 | |a Chromones |2 NLM | |
| 650 | 7 | |a ICAM1 protein, human |2 NLM | |
| 650 | 7 | |a Morpholines |2 NLM | |
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| 650 | 7 | |a 31M2U1DVID |2 NLM | |
| 650 | 7 | |a NOS3 protein, human |2 NLM | |
| 650 | 7 | |a EC 1.14.13.39 |2 NLM | |
| 650 | 7 | |a Nitric Oxide Synthase Type III |2 NLM | |
| 650 | 7 | |a EC 1.14.13.39 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a p38 Mitogen-Activated Protein Kinases |2 NLM | |
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| 650 | 7 | |a NG-Nitroarginine Methyl Ester |2 NLM | |
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| 700 | 1 | |a Wei, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Hong, Chengcheng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xuguo |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Fang |e verfasserin |4 aut | |
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