Pulmonary surfactant protein D inhibits lipopolysaccharide (LPS)-induced inflammatory cell responses by altering LPS binding to its receptors.
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.
Yamazoe
Masami
M
Department of Biochemistry, Sapporo Medical University School of Medicine, South 1, West 17, Sapporo 060-8556, Japan.
Nishitani
Chiaki
C
Takahashi
Motoko
M
Katoh
Tsuyoshi
T
Ariki
Shigeru
S
Shimizu
Takeyuki
T
Mitsuzawa
Hiroaki
H
Sawada
Kaku
K
Voelker
Dennis R
DR
Takahashi
Hiroki
H
Kuroki
Yoshio
Y
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
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