Surfactant protein a inhibits lipopolysaccharide-induced immune cell activation by preventing the interaction of lipopolysaccharide with lipopolysaccharide-binding protein.
Pulmonary surfactant protein (SP)-A, an innate immune molecule, modifies lipopolysaccharide (LPS)-induced cell responses. Because SP-A avidly binds to the deep rough (Re) mutant of LPS, we first investigated the functional consequences of this interaction and found that preincubation of Re-LPS with SP-A significantly and in a dose-dependent manner decreased the sensitivity of rat alveolar macrophages and human mononuclear cells to Re-LPS-induced activation at limited amounts of LPS-binding protein (LBP). At high LBP concentrations, the SP-A-mediated cellular inhibition of Re-LPS-induced activation was abrogated. Because LBP-catalyzed binding of LPS to CD14 is essential for low-dose LPS-induced signaling, we then hypothesized that SP-A inhibits Re-LPS-induced immune cell activation via inhibiting the binding of Re-LPS to LBP. Binding competition experiments employing a surface plasmon resonance technique showed that Re-LPS preincubated with SP-A bound to LBP to a significantly lesser extent than Re-LPS alone. For enhanced cellular association of [(3)H]LPS/SP-A complexes to occur, the expression of membrane-bound CD14 by human embryonic kidney cells 293 was not essential. Therefore, the ability of SP-A to inhibit immune cell activation by Re-LPS may be due to its ability to block the binding of Re-LPS to LBP and prevent the initiation of the LBP/CD14 pathway for inflammatory reactions in the lung.
Department of Immunochemistry and Biochemical Microbiology, Research Center Borstel, Center for Medicine and Bioscience, Borstel, Germany. cstamme@fz-borstel.de
Cordula
C
Stamme
Mareike
M
Müller
Lutz
L
Hamann
Thomas
T
Gutsmann
Ulrich
U
Seydel
D000209:Acute-Phase Proteins; D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D007107:Immune System / Q000166:cytology* / Q000187:drug effects; D007111:Immunity, Cellular / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D011510:Proteolipids / Q000494:pharmacology*; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010743:Phospholipids; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D014409:Tumor Necrosis Factor-alpha; D000099231:Lipopolysaccharide-Binding Protein