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Cytokines induce upregulation of vascular P2Y(2) receptors and increased mitogenic responses to UTP and ATP

Hou, M; Moller, S; Edvinsson, Lars LU and Erlinge, David LU (2000) In Arteriosclerosis, Thrombosis and Vascular Biology 20(9). p.2064-2069
Abstract
P2Y(2) receptors, which mediate contractile and mitogenic effects of extracellular nucleotides in vascular smooth muscle cells (VSMCs), are upregulated in the synthetic phenotype of VSMCs and in the neointima after balloon angioplasty, suggesting a role in the development of atherosclerosis. Because released cytokines in atherosclerotic lesions mediate multiple effects on gene transcription in VSMCs, we speculated that cytokines could be involved in the regulation of P2Y(2) receptor expression. Using a competitive reverse transcription-polymerase chain reaction, we detected that interleukin (IL)-1beta induced a time- and dose-dependent upregulation of P2Y(2) receptor mRNA, which was dramatically enhanced when combined with interferon-gamma... (More)
P2Y(2) receptors, which mediate contractile and mitogenic effects of extracellular nucleotides in vascular smooth muscle cells (VSMCs), are upregulated in the synthetic phenotype of VSMCs and in the neointima after balloon angioplasty, suggesting a role in the development of atherosclerosis. Because released cytokines in atherosclerotic lesions mediate multiple effects on gene transcription in VSMCs, we speculated that cytokines could be involved in the regulation of P2Y(2) receptor expression. Using a competitive reverse transcription-polymerase chain reaction, we detected that interleukin (IL)-1beta induced a time- and dose-dependent upregulation of P2Y(2) receptor mRNA, which was dramatically enhanced when combined with interferon-gamma or tumor necrosis factor-alpha. Lipopolysaccharide also significantly increased the expression of P2Y(2) receptor mRNA. The upregulation of P2Y(2) receptor mRNA was paralleled at the functional level because IL-1beta significantly increased the UTP-stimulated DNA synthesis and the release of intracellular Ca(2+). Actinomycin D completely blocked the upregulation of P2Y(2) receptor mRNA expression by IL-1beta, indicating de novo mRNA synthesis. There was no cAMP accumulation in the cells stimulated with IL-1beta. The cyclooxygenase inhibitor indomethacin and the protein kinase C inhibitor RO-31-8220 inhibited IL-1beta-induced upregulation of P2Y(2) receptor mRNA expression, whereas rapamycin and PD098059 had no effects. Furthermore, neither P38 mitogen-activated protein kinase inhibitor SB20358 alone nor its combination with PD098059 blocked the effect of IL-1beta on the expression of P2Y(2) receptor mRNA. Our results demonstrate that inflammatory mediators upregulate vascular P2Y(2) receptors at the transcriptional and at the functional level through protein kinase C and cyclooxygenase but not cAMP, extracellular signal-regulated kinases 1 and 2, or P38-dependent pathways. This may result in increased growth-stimulatory or contractile effects of extracellular UTP and ATP, which may be of importance in the development of vascular disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
P2Y2 receptors n interleukin-1b n competitive reverse transcription–polymerase chain reaction
in
Arteriosclerosis, Thrombosis and Vascular Biology
volume
20
issue
9
pages
2064 - 2069
publisher
American Heart Association
external identifiers
  • pmid:10978250
  • scopus:0033812131
ISSN
1524-4636
language
English
LU publication?
yes
id
88dcbb6b-2f01-41b3-8a78-a2ddac1c36c7 (old id 1117306)
alternative location
http://atvb.ahajournals.org/cgi/content/full/20/9/2064
date added to LUP
2008-07-03 10:57:21
date last changed
2017-06-11 03:25:00
@article{88dcbb6b-2f01-41b3-8a78-a2ddac1c36c7,
  abstract     = {P2Y(2) receptors, which mediate contractile and mitogenic effects of extracellular nucleotides in vascular smooth muscle cells (VSMCs), are upregulated in the synthetic phenotype of VSMCs and in the neointima after balloon angioplasty, suggesting a role in the development of atherosclerosis. Because released cytokines in atherosclerotic lesions mediate multiple effects on gene transcription in VSMCs, we speculated that cytokines could be involved in the regulation of P2Y(2) receptor expression. Using a competitive reverse transcription-polymerase chain reaction, we detected that interleukin (IL)-1beta induced a time- and dose-dependent upregulation of P2Y(2) receptor mRNA, which was dramatically enhanced when combined with interferon-gamma or tumor necrosis factor-alpha. Lipopolysaccharide also significantly increased the expression of P2Y(2) receptor mRNA. The upregulation of P2Y(2) receptor mRNA was paralleled at the functional level because IL-1beta significantly increased the UTP-stimulated DNA synthesis and the release of intracellular Ca(2+). Actinomycin D completely blocked the upregulation of P2Y(2) receptor mRNA expression by IL-1beta, indicating de novo mRNA synthesis. There was no cAMP accumulation in the cells stimulated with IL-1beta. The cyclooxygenase inhibitor indomethacin and the protein kinase C inhibitor RO-31-8220 inhibited IL-1beta-induced upregulation of P2Y(2) receptor mRNA expression, whereas rapamycin and PD098059 had no effects. Furthermore, neither P38 mitogen-activated protein kinase inhibitor SB20358 alone nor its combination with PD098059 blocked the effect of IL-1beta on the expression of P2Y(2) receptor mRNA. Our results demonstrate that inflammatory mediators upregulate vascular P2Y(2) receptors at the transcriptional and at the functional level through protein kinase C and cyclooxygenase but not cAMP, extracellular signal-regulated kinases 1 and 2, or P38-dependent pathways. This may result in increased growth-stimulatory or contractile effects of extracellular UTP and ATP, which may be of importance in the development of vascular disease.},
  author       = {Hou, M and Moller, S and Edvinsson, Lars and Erlinge, David},
  issn         = {1524-4636},
  keyword      = {P2Y2 receptors n interleukin-1b n competitive reverse transcription–polymerase chain reaction},
  language     = {eng},
  number       = {9},
  pages        = {2064--2069},
  publisher    = {American Heart Association},
  series       = {Arteriosclerosis, Thrombosis and Vascular Biology},
  title        = {Cytokines induce upregulation of vascular P2Y(2) receptors and increased mitogenic responses to UTP and ATP},
  volume       = {20},
  year         = {2000},
}