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TNF-alpha-induced self expression in human lung endothelial cells is inhibited by native and oxidized alpha 1-antitrypsin

Subramaniyam, Devipriya LU ; Virtala, Robert; Pawlowski, Krzysztof; Clausen, Ib Groth; Warkentin, Siegbert LU ; Stevens, Tim and Janciauskiene, Sabina LU (2008) In International Journal of Biochemistry & Cell Biology 40(2). p.258-271
Abstract
Endothelial cells are among the main physiological targets of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). In endothelial cells TNF-alpha elicits a broad spectrum of biological effects including differentiation, proliferation and apoptosis. alpha 1-antitrypsin (AAT), an endogenous inhibitor of serine proteases plays a vital role in protecting host tissue from proteolytic injury at sites of inflammation. Recently, it has been shown that AAT can be internalized by pulmonary endothelial cells, raising speculation that it may modulate endothelial cell function in addition to suppressing protease activity. Using Affymetrix microarray technology, real time PCR and ELISA methods we have investigated the effects of AAT on... (More)
Endothelial cells are among the main physiological targets of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). In endothelial cells TNF-alpha elicits a broad spectrum of biological effects including differentiation, proliferation and apoptosis. alpha 1-antitrypsin (AAT), an endogenous inhibitor of serine proteases plays a vital role in protecting host tissue from proteolytic injury at sites of inflammation. Recently, it has been shown that AAT can be internalized by pulmonary endothelial cells, raising speculation that it may modulate endothelial cell function in addition to suppressing protease activity. Using Affymetrix microarray technology, real time PCR and ELISA methods we have investigated the effects of AAT on un-stimulated and TNF-alpha stimulated human primary lung microvascular endothelial cell gene expression and protein secretion. We find that AAT and TNF-alpha generally induced expression of distinct gene families with AAT exhibiting little activity in terms of inflammatory gene expression. Approximately 25% of genes up regulated by TNF-alpha were inhibited by co-administration of AAT including TNF-alpha-induced self expression. Surprisingly, the effects of AAT on TNF-alpha-induced self expression was inhibited equally well by oxidized AAT, a modified form of AAT, which lacks serine protease inhibitor activity. Overall, the pattern of gene expression regulated by native and oxidized AAT was similar with neither inducing pro-inflammatory gene expression. These findings suggest that inhibitory effects of native and oxidized forms of AAT on TNF-alpha stimulated gene expression may play an important role in limiting the uncontrolled endothelial cell activation and vascular injury in inflammatory disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
alpha 1-Antitrypsin, affymetrix microarray technology, inflammation, oxidized, lung microvascular endothelial cells
in
International Journal of Biochemistry & Cell Biology
volume
40
issue
2
pages
258 - 271
publisher
Elsevier
external identifiers
  • wos:000252061800011
  • scopus:36248935622
ISSN
1878-5875
DOI
10.1016/j.biocel.2007.07.016
language
English
LU publication?
yes
id
069bf33f-590e-4c5e-9980-10546fa6b1f3 (old id 1200208)
date added to LUP
2008-09-12 11:44:20
date last changed
2017-10-01 04:03:28
@article{069bf33f-590e-4c5e-9980-10546fa6b1f3,
  abstract     = {Endothelial cells are among the main physiological targets of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). In endothelial cells TNF-alpha elicits a broad spectrum of biological effects including differentiation, proliferation and apoptosis. alpha 1-antitrypsin (AAT), an endogenous inhibitor of serine proteases plays a vital role in protecting host tissue from proteolytic injury at sites of inflammation. Recently, it has been shown that AAT can be internalized by pulmonary endothelial cells, raising speculation that it may modulate endothelial cell function in addition to suppressing protease activity. Using Affymetrix microarray technology, real time PCR and ELISA methods we have investigated the effects of AAT on un-stimulated and TNF-alpha stimulated human primary lung microvascular endothelial cell gene expression and protein secretion. We find that AAT and TNF-alpha generally induced expression of distinct gene families with AAT exhibiting little activity in terms of inflammatory gene expression. Approximately 25% of genes up regulated by TNF-alpha were inhibited by co-administration of AAT including TNF-alpha-induced self expression. Surprisingly, the effects of AAT on TNF-alpha-induced self expression was inhibited equally well by oxidized AAT, a modified form of AAT, which lacks serine protease inhibitor activity. Overall, the pattern of gene expression regulated by native and oxidized AAT was similar with neither inducing pro-inflammatory gene expression. These findings suggest that inhibitory effects of native and oxidized forms of AAT on TNF-alpha stimulated gene expression may play an important role in limiting the uncontrolled endothelial cell activation and vascular injury in inflammatory disease.},
  author       = {Subramaniyam, Devipriya and Virtala, Robert and Pawlowski, Krzysztof and Clausen, Ib Groth and Warkentin, Siegbert and Stevens, Tim and Janciauskiene, Sabina},
  issn         = {1878-5875},
  keyword      = {alpha 1-Antitrypsin,affymetrix microarray technology,inflammation,oxidized,lung microvascular endothelial cells},
  language     = {eng},
  number       = {2},
  pages        = {258--271},
  publisher    = {Elsevier},
  series       = {International Journal of Biochemistry & Cell Biology},
  title        = {TNF-alpha-induced self expression in human lung endothelial cells is inhibited by native and oxidized alpha 1-antitrypsin},
  url          = {http://dx.doi.org/10.1016/j.biocel.2007.07.016},
  volume       = {40},
  year         = {2008},
}