title: α1-antitrypsin production by proinflammatory and antiinflammatory macrophages and dendritic cells.
abstract: α(1)-Antitrypsin (AAT) acts as an important neutrophil elastase inhibitor in the lung. Although the hepatocyte is considered to be the primary source of AAT, local production by monocytes, macrophages, and epithelial cells may contribute to the formation of an antielastase screen. Because monocytes can differentiate into a heterogeneous population of macrophages with subpopulations ranging from proinflammatory properties (MΦ-1) to antiinflammatory properties (ΜΦ-2) and into dendritic cells (DCs), we studied whether LPS, TNF-α, and oncostatin M (OSM) enhance AAT production differentially in cultured ΜΦ-1, ΜΦ-2, and DCs. Monocytes from healthy blood donors were cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor, or GM-CSF with IL-4 to obtain ΜΦ-1, ΜΦ-2, and immature (i)DCs, respectively. Cells were stimulated with LPS, TNF-α, or OSM, and AAT synthesis was assessed by quantitative RT-PCR, immunocytochemistry, and ELISA. Spontaneous release of AAT was higher in ΜΦ-1 than in ΜΦ-2 and iDCs, and only LPS significantly increased AAT production in ΜΦ-1, ΜΦ-2, and DC. TNF-α and OSM did not affect AAT secretion. The secretion levels of the related protease inhibitors α-1 antichymotrypsin and secretory leukocyte proteinase inhibitor were below the limits of detection by ELISA. In contrast to the protein data, analysis by quantitative RT-PCR showed that 24-hour LPS exposure caused a maximal 2.1-fold AAT mRNA increase in ΜΦ-1, a 21-fold increase in ΜΦ-2, and an 11-fold increase in DCs. These data suggest that cellular differentiation is a regulator of local AAT production.
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Emily F A
authors.initials: EF
authors.lastname: van 't Wout
authors.forename: Annemarie
authors.initials: A
authors.lastname: van Schadewijk
authors.forename: Nigel D L
authors.initials: ND
authors.lastname: Savage
authors.forename: Jan
authors.initials: J
authors.lastname: Stolk
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
mesh_terms: D001992:Bronchoalveolar Lavage Fluid; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D000515:alpha 1-Antitrypsin / Q000096:biosynthesis*
chemical_list: D000515:alpha 1-Antitrypsin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor