Surfactant protein a inhibits lipopolysaccharide-induced immune cell activation by preventing the interaction of lipopolysaccharide with lipopolysaccharide-binding protein

Am J Respir Cell Mol Biol. 2002 Sep;27(3):353-60. doi: 10.1165/rcmb.4812.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins*
  • Animals
  • Binding, Competitive
  • Carrier Proteins / drug effects
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Humans
  • Immune System / cytology*
  • Immune System / drug effects
  • Immunity, Cellular / immunology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Lipopolysaccharide Receptors / drug effects
  • Lipopolysaccharide Receptors / genetics
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharides / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / immunology
  • Male
  • Membrane Glycoproteins*
  • Monocytes / drug effects
  • Monocytes / immunology
  • Monocytes / metabolism
  • Mutation
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Phospholipids / chemistry
  • Phospholipids / metabolism
  • Proteolipids / pharmacology*
  • Pulmonary Surfactant-Associated Protein A
  • Pulmonary Surfactant-Associated Proteins
  • Pulmonary Surfactants / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Acute-Phase Proteins
  • Carrier Proteins
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • NF-kappa B
  • Phospholipids
  • Proteolipids
  • Pulmonary Surfactant-Associated Protein A
  • Pulmonary Surfactant-Associated Proteins
  • Pulmonary Surfactants
  • Tumor Necrosis Factor-alpha
  • lipopolysaccharide-binding protein