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Concentration-dependent effects of native and polymerised alpha 1-antitrypsin on primary human monocytes, in vitro

Aldonyte, Ruta LU ; Jansson, Lennart LU and Janciauskiene, Sabina LU (2004) In BMC Cell Biology 5.
Abstract
Background: alpha1-antitrypsin (AAT) is one of the major serine proteinase inhibitors controlling proteinases in many biological pathways. There is increasing evidence that AAT is able to exert other than antiproteolytic effects. To further examine this question we compared how various doses of the native (inhibitory) and the polymerised (non- inhibitory) molecular form of AAT affect pro-inflammatory responses in human monocytes, in vitro. Human monocytes isolated from different donors were exposed to the native or polymerised form of AAT at concentrations of 0.01, 0.02, 0.05, 0.1, 0.5 and 1 mg/ml for 18 h, and analysed to determine the release of cytokines and to detect the activity of NF-kappaB. Results: We found that native and... (More)
Background: alpha1-antitrypsin (AAT) is one of the major serine proteinase inhibitors controlling proteinases in many biological pathways. There is increasing evidence that AAT is able to exert other than antiproteolytic effects. To further examine this question we compared how various doses of the native (inhibitory) and the polymerised (non- inhibitory) molecular form of AAT affect pro-inflammatory responses in human monocytes, in vitro. Human monocytes isolated from different donors were exposed to the native or polymerised form of AAT at concentrations of 0.01, 0.02, 0.05, 0.1, 0.5 and 1 mg/ml for 18 h, and analysed to determine the release of cytokines and to detect the activity of NF-kappaB. Results: We found that native and polymerised AAT at lower concentrations, such as 0.1 mg/ml, enhance expression of TNFalpha (10.9- and 4.8-fold, p < 0.001), IL-6 (22.8- and 23.4-fold, p < 0.001), IL-8 (2.4- and 5.5-fold, p < 0.001) and MCP-1 (8.3- and 7.7-fold, p < 0.001), respectively, compared to buffer exposed cells or cells treated with higher doses of AAT ( 0.5 and 1 mg/ml). In parallel to increased cytokine levels, low concentrations of either conformation of AAT (0.02-0.1 mg/ml) induced NF-kappaB p50 activation, while 1 mg/ml of either conformation of AAT suppressed the activity of NF-kappaB, compared to controls. Conclusions: The observations reported here provide further support for a central role of AAT in inflammation, both as a regulator of proteinase activity, and as a signalling molecule for the expression of pro-inflammatory molecules. This latter role is dependent on the concentration of AAT, rather than on its proteinase inhibitory activity. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
BMC Cell Biology
volume
5
publisher
BioMed Central
external identifiers
  • pmid:15050036
  • wos:000221186700001
  • scopus:2342667393
ISSN
1471-2121
DOI
10.1186/1471-2121-5-11
language
English
LU publication?
yes
id
c72bfcde-79f7-4fd9-9fff-1ac29c747e31 (old id 279992)
date added to LUP
2007-09-03 11:24:36
date last changed
2017-02-05 04:12:44
@article{c72bfcde-79f7-4fd9-9fff-1ac29c747e31,
  abstract     = {Background: alpha1-antitrypsin (AAT) is one of the major serine proteinase inhibitors controlling proteinases in many biological pathways. There is increasing evidence that AAT is able to exert other than antiproteolytic effects. To further examine this question we compared how various doses of the native (inhibitory) and the polymerised (non- inhibitory) molecular form of AAT affect pro-inflammatory responses in human monocytes, in vitro. Human monocytes isolated from different donors were exposed to the native or polymerised form of AAT at concentrations of 0.01, 0.02, 0.05, 0.1, 0.5 and 1 mg/ml for 18 h, and analysed to determine the release of cytokines and to detect the activity of NF-kappaB. Results: We found that native and polymerised AAT at lower concentrations, such as 0.1 mg/ml, enhance expression of TNFalpha (10.9- and 4.8-fold, p &lt; 0.001), IL-6 (22.8- and 23.4-fold, p &lt; 0.001), IL-8 (2.4- and 5.5-fold, p &lt; 0.001) and MCP-1 (8.3- and 7.7-fold, p &lt; 0.001), respectively, compared to buffer exposed cells or cells treated with higher doses of AAT ( 0.5 and 1 mg/ml). In parallel to increased cytokine levels, low concentrations of either conformation of AAT (0.02-0.1 mg/ml) induced NF-kappaB p50 activation, while 1 mg/ml of either conformation of AAT suppressed the activity of NF-kappaB, compared to controls. Conclusions: The observations reported here provide further support for a central role of AAT in inflammation, both as a regulator of proteinase activity, and as a signalling molecule for the expression of pro-inflammatory molecules. This latter role is dependent on the concentration of AAT, rather than on its proteinase inhibitory activity.},
  author       = {Aldonyte, Ruta and Jansson, Lennart and Janciauskiene, Sabina},
  issn         = {1471-2121},
  language     = {eng},
  publisher    = {BioMed Central},
  series       = {BMC Cell Biology},
  title        = {Concentration-dependent effects of native and polymerised alpha 1-antitrypsin on primary human monocytes, in vitro},
  url          = {http://dx.doi.org/10.1186/1471-2121-5-11},
  volume       = {5},
  year         = {2004},
}