title: Pulmonary surfactant protein D inhibits lipopolysaccharide (LPS)-induced inflammatory cell responses by altering LPS binding to its receptors.
abstract: Pulmonary surfactant protein D (SP-D) is a member of the collectin family that plays an important role in regulating innate immunity of the lung. We examined the mechanisms by which SP-D modulates lipopolysaccharide (LPS)-elicited inflammatory cell responses. SP-D bound to a complex of recombinant soluble forms of Toll-like receptor 4 (TLR4) and MD-2 with high affinity and down-regulated tumor necrosis factor-alpha secretion and NF-kappaB activation elicited by rough and smooth LPS, in alveolar macrophages and TLR4/MD-2-transfected HEK293 cells. Cell surface binding of both serotypes of LPS to TLR4/MD-2-expressing cells was attenuated by SP-D. In addition, SP-D significantly reduced MD-2 binding to both serotypes of LPS. A chimera containing the N-terminal region and the collagenous domain of surfactant protein A, and the coiled-coil neck and lectin domains of SP-D, was a weak inhibitor of LPS-induced cell responses and MD-2 binding to LPS, compared with native SP-D. The collagenase-resistant fragment consisting of the neck plus the carbohydrate recognition domain of SP-D also was a very weak inhibitor of LPS activation. This study demonstrates that SP-D down-regulates LPS-elicited inflammatory responses by altering LPS binding to its receptors and reveals the importance of the correct oligomeric structure of the protein in this process.
authors.affiliation: Department of Biochemistry, Sapporo Medical University School of Medicine, South 1, West 17, Sapporo 060-8556, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Yamazoe
authors.forename: Chiaki
authors.initials: C
authors.lastname: Nishitani
authors.forename: Motoko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Katoh
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ariki
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Shimizu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuzawa
authors.forename: Kaku
authors.initials: K
authors.lastname: Sawada
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Voelker
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kuroki
mesh_terms: D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology* / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000276:immunology*; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics / Q000276:immunology; D037663:Pulmonary Surfactant-Associated Protein D / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D011993:Recombinant Fusion Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha