PMID- 31289638
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220409
IS  - 2045-3701 (Print)
IS  - 2045-3701 (Electronic)
IS  - 2045-3701 (Linking)
VI  - 9
DP  - 2019
TI  - Regulation of platelet-activating factor-mediated interleukin-6 promoter 
      activation by the 48 kDa but not the 45 kDa isoform of protein tyrosine 
      phosphatase non-receptor type 2.
PG  - 51
LID - 10.1186/s13578-019-0316-9 [doi]
LID - 51
AB  - BACKGROUND: An underlying state of inflammation is thought to be an important 
      cause of cardiovascular disease. Among cells involved in the early steps of 
      atherosclerosis, monocyte-derived dendritic cells (Mo-DCs) respond to 
      inflammatory stimuli, including platelet-activating factor (PAF), by the 
      induction of various cytokines, such as interleukin 6 (IL-6). PAF is a potent 
      phospholipid mediator involved in both the onset and progression of 
      atherosclerosis. It mediates its effects by binding to its cognate G-protein 
      coupled receptor, PAFR. Activation of PAFR-induced signaling pathways is tightly 
      coordinated to ensure specific cell responses. RESULTS: Here, we report that PAF 
      stimulated the phosphatase activity of both the 45 and 48 kDa isoforms of the 
      protein tyrosine phosphatase non-receptor type 2 (PTPN2). However, we found that 
      only the 48 kDa PTPN2 isoform has a role in PAFR-induced signal transduction, 
      leading to activation of the IL-6 promoter. In luciferase reporter assays, 
      expression of the 48 kDa, but not the 45 kDa, PTPN2 isoform increased human IL-6 
      (hIL-6) promoter activity by 40% after PAF stimulation of HEK-293 cells, stably 
      transfected with PAFR (HEK-PAFR). Our results suggest that the differential 
      localization of the PTPN2 isoforms and the differences in PAF-induced phosphatase 
      activation may contribute to the divergent modulation of PAF-induced IL-6 
      promoter activation. The involvement of PTPN2 in PAF-induced IL-6 expression was 
      confirmed in immature Mo-DCs (iMo-DCs), using siRNAs targeting the two isoforms 
      of PTPN2, where siRNAs against the 48 kDa PTPN2 significantly inhibited 
      PAF-stimulated IL-6 mRNA expression. Pharmacological inhibition of several 
      signaling pathways suggested a role for PTPN2 in early signaling events. Results 
      obtained by Western blot confirmed that PTPN2 increased the activation of the 
      PI3K/Akt pathway via the modulation of protein kinase D (PKD) activity. WT PKD 
      expression counteracted the effect of PTPN2 on PAF-induced IL-6 promoter 
      transactivation and phosphorylation of Akt. Using siRNAs targeting the individual 
      isoforms of PTPN2, we confirmed that these pathways were also active in iMo-DCs. 
      CONCLUSION: Taken together, our data suggest that PTPN2, in an isoform-specific 
      manner, could be involved in the positive regulation of PI3K/Akt activation, via 
      the modulation of PKD activity, allowing for the maximal induction of 
      PAF-stimulated IL-6 mRNA expression.
FAU - Hamel-Cote, Genevieve
AU  - Hamel-Cote G
AD  - Immunology Division, Department of Pediatrics, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke, Sherbrooke, QC Canada. ISNI: 0000 0000 9064 
      6198. GRID: grid.86715.3d
FAU - Lapointe, Fanny
AU  - Lapointe F
AD  - Immunology Division, Department of Pediatrics, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke, Sherbrooke, QC Canada. ISNI: 0000 0000 9064 
      6198. GRID: grid.86715.3d
FAU - Veronneau, Steeve
AU  - Veronneau S
AD  - Immunology Division, Department of Pediatrics, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke, Sherbrooke, QC Canada. ISNI: 0000 0000 9064 
      6198. GRID: grid.86715.3d
FAU - Mayhue, Marian
AU  - Mayhue M
AD  - Immunology Division, Department of Pediatrics, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke, Sherbrooke, QC Canada. ISNI: 0000 0000 9064 
      6198. GRID: grid.86715.3d
FAU - Rola-Pleszczynski, Marek
AU  - Rola-Pleszczynski M
AD  - Immunology Division, Department of Pediatrics, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke, Sherbrooke, QC Canada. ISNI: 0000 0000 9064 
      6198. GRID: grid.86715.3d
FAU - Stankova, Jana
AU  - Stankova J
AUID- ORCID: 0000-0002-4127-8506
AD  - Immunology Division, Department of Pediatrics, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke, Sherbrooke, QC Canada. ISNI: 0000 0000 9064 
      6198. GRID: grid.86715.3d
LA  - eng
PT  - Journal Article
DEP - 20190625
PL  - England
TA  - Cell Biosci
JT  - Cell & bioscience
JID - 101561195
PMC - PMC6593612
OTO - NOTNLM
OT  - GPCR
OT  - IL-6
OT  - PTPN2
OT  - Platelet-activating factor
OT  - Protein tyrosine phosphatase
OT  - TC-PTP
COIS- Competing interestsThe authors declare that they have no competing interests.
EDAT- 2019/07/11 06:00
MHDA- 2019/07/11 06:01
PMCR- 2019/06/25
CRDT- 2019/07/11 06:00
PHST- 2019/02/21 00:00 [received]
PHST- 2019/06/20 00:00 [accepted]
PHST- 2019/07/11 06:00 [entrez]
PHST- 2019/07/11 06:00 [pubmed]
PHST- 2019/07/11 06:01 [medline]
PHST- 2019/06/25 00:00 [pmc-release]
AID - 316 [pii]
AID - 10.1186/s13578-019-0316-9 [doi]
PST - epublish
SO  - Cell Biosci. 2019 Jun 25;9:51. doi: 10.1186/s13578-019-0316-9. eCollection 2019.