Activation of primary human monocytes by the oxidized form of alpha1-antitrypsin.
The oxidation of methionine residues in many proteins, including the serine proteinase inhibitor alpha1-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-alpha 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 (125)I-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.
Moraga
F
F
Gastroenterology-Hepatology Section, Department of Medicine, University Hospital Malmö, 20502 Malmö, Sweden.
Janciauskiene
S
S
D018955:CD36 Antigens / Q000096:biosynthesis; D018932:Chemokine CCL2 / Q000096:biosynthesis; D002784:Cholesterol / Q000096:biosynthesis; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D008077:Lipoproteins, LDL / Q000378:metabolism; D008565:Membrane Proteins; D009000:Monocytes / Q000187:drug effects*; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D011971:Receptors, Immunologic / Q000096:biosynthesis; D011973:Receptors, LDL / Q000096:biosynthesis; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000494:pharmacology*
D018955:CD36 Antigens; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D015850:Interleukin-6; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D002784:Cholesterol; D019255:NADPH Oxidases