title: Pulmonary surfactant protein A activates a phosphatidylinositol 3-kinase/calcium signal transduction pathway in human macrophages: participation in the up-regulation of mannose receptor activity.
abstract: Surfactant protein A (SP-A), a major component of lung surfactant, binds to macrophages and has been shown to alter several macrophage biological functions, including up-regulation of macrophage mannose receptor (MR) activity. In the present study, we show that SP-A induces signal transduction pathway(s) that impact on MR expression. The addition of human, rat, or recombinant rat SP-A to human monocyte-derived macrophages significantly raised the level of cytosolic Ca2+ above baseline within 10 s of SP-A addition, as measured by spectrofluorometric analysis. SP-A induced a refractory state specific for SP-A consistent with homologous desensitization of a receptor(s) linked to calcium mobilization because a second application of SP-A did not induce a rise in cytosolic Ca2+ whereas the addition of platelet-activating factor did. Using site-directed mutations in SP-A, we determined that both the attached sugars and the collagen-like domain of SP-A are necessary to optimize Ca2+ mobilization. SP-A triggered the increase in cytosolic Ca2+ by inducing activation of phospholipase C, which leads to the hydrolysis of membrane phospholipids, yielding inositol 1,4,5-trisphosphate and mobilizing intracellularly stored Ca2+ by inositol triphosphate-sensitive channels. Finally, inhibition of PI3Ks, which appear to act upstream of phospholipase C in Ca2+ mobilization, decreased the SP-A-induced rise in MR expression, providing evidence that SP-A induction of MR activity involves the activation of a pathway in which PI3K is a component. These studies provide further evidence that SP-A produced in the lung plays a role in modulating macrophage biology, thereby contributing to the alternative activation state of the alveolar macrophage.
authors.affiliation: Interdisciplinary Program in Immunology and Department of Internal Medicine, University of Iowa, Iowa City, IA 52240, USA.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Beharka
authors.forename: Joy E
authors.initials: JE
authors.lastname: Crowther
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
authors.forename: Gerene M
authors.initials: GM
authors.lastname: Denning
authors.forename: Jason
authors.initials: J
authors.lastname: Lees
authors.forename: Eric
authors.initials: E
authors.lastname: Tibesar
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
mesh_terms: D000328:Adult; D000818:Animals; D001665:Binding Sites / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology*; D003094:Collagen / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism / Q000502:physiology; D007424:Intracellular Fluid / Q000378:metabolism; D037181:Lectins, C-Type / Q000096:biosynthesis* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000096:biosynthesis* / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D009844:Oligosaccharides / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000378:metabolism; D020298:U937 Cells; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D002118:Calcium; D003094:Collagen; D015544:Inositol 1,4,5-Trisphosphate; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009844:Oligosaccharides; D019869:Phosphatidylinositol 3-Kinases; D037662:Pulmonary Surfactant-Associated Protein A; D011956:Receptors, Cell Surface