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Surfactant Protein A Inhibits Lipopolysaccharide-Induced Immune Cell Activation by Preventing the Interaction of Lipopolysaccharide with Lipopolysaccharide-Binding Protein

Department of Immunochemistry and Biochemical Microbiology, Research Center Borstel, Center for Medicine and Bioscience, Borstel; Department of Anesthesiology, University Hospital Lübeck, Lübeck; Department of Immunology and Cell Biology, Research Center Borstel, Borstel; and Department of Microbiology and Hygiene, Charité Medical Center, Humboldt University Berlin, Berlin, Germany

Address correspondence to: Dr. Cordula Stamme, Dept. of Immunochemistry and Biochemical Microbiology, Research Center Borstel, Parkallee 22, 23845 Borstel, Germany. E-mail: cstamme{at}fz-borstel.de

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 [³H]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.

Abbreviations: Dulbecco's modified Eagle's medium, DMEM • Dulbecco's phosphate-buffered saline, DPBS • electrophoretic mobility shift assay, EMSA • fetal calf serum, FCS • human embryonic kidney, HEK • lipopolysaccharide, LPS • LPS-binding protein, LBP • membrane-bound CD14, mCD14 • nuclear factor B, NF-B • phosphatidylserine, PS • Rb mutant of Escherichia coli strain LCD 25 LPS, Rb-LPS • Re mutant of Escherichia coli strain F515, Re-LPS • recombinant human, rh • soluble CD14, sCD14 • surfactant protein, SP • surface plasmon resonance, SPR • tumor necrosis factor, TNF

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