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J Biol Chem, Vol. 275, Issue 11, 7693-7700, March 17, 2000
From the Gastroenterology-Hepatology Section, Department of
Medicine, University Hospital Malmö,
20502 Malmö, Sweden
The oxidation of methionine residues in many
proteins, including the serine proteinase inhibitor
Activation of Primary Human Monocytes by the Oxidized Form of
1-Antitrypsin*
1-antitrypsin
(AAT), can result in functional inactivation. In this study we
investigated the pro-inflammatory properties of oxidized AAT (oxAAT),
specifically its ability to activate human monocytes in culture.
Monocytes stimulated with oxAAT at concentrations up to 0.2 mg/ml for
24 h showed significant elevation in monocyte chemoattractant
protein-1, cytokine interleukin-6, and tumor necrosis factor-
expression and increased NADPH oxidase activity. Monocytes activated
with oxAAT showed surprising effects on lipid metabolism. Expression of
low density lipoprotein (LDL) receptors increased by up to 76%
compared with controls but was not accompanied by any changes in
125I-labeled LDL binding and, paradoxically,
decreased LDL uptake, degradation, and intracellular cholesterol
synthesis. oxAAT also down-regulated the scavenger receptor CD36, which
takes up and is up-regulated by oxidized LDL and is down-regulated by
cholesterol efflux. As a by-product of oxidative events accompanying
inflammation, oxAAT has multiple effects on cytokine expression,
generation of reactive oxygen species, and on intracellular lipid
metabolism. The up-regulation of monocyte-derived reactive oxygen by
oxAAT could potentially result in self-amplification of AAT oxidation and, thereby, the other effects deriving from it. This implies that
there are as yet unidentified regulatory processes that control this cycle.
*
This work was supported by the Faculty of Medicine, Lund
University and Swedish Medical Research Foundation Grants
K99-72X-13140-01A and K1999-03P-013008-01A).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed:
Gastroenterology-Hepatology Division, Dept. of Medicine, Wallenberg
Lab., Ing.46, MAS, S-20502, Malmö, Sweden. Tel.: 46-40-33-14-14;
Fax: 46-40-33-70-41; E-mail:
Sabina.Janciauskiene@medforsk.mas.lu.se.
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