title: Surfactant protein A inhibits peptidoglycan-induced tumor necrosis factor-alpha secretion in U937 cells and alveolar macrophages by direct interaction with toll-like receptor 2.
abstract: Pulmonary surfactant protein A (SP-A) plays an important role in modulation of the innate immune system of the lung. Peptidoglycan (PGN), a cell wall component of Gram-positive bacteria, is known to elicit excessive proinflammatory cytokine production from immune cells. In this study we investigated whether SP-A interacts with PGN and alters PGN-elicited cellular responses. Binding studies demonstrate that PGN is not a ligand for SP-A. However, SP-A significantly reduced PGN-elicited tumor necrosis factor alpha (TNF-alpha) secretion by U937 cells and rat alveolar macrophages. The inhibitory effect on TNF-alpha secretion was dependent upon SP-A concentrations in physiological range. Coincubation of SP-A and PGN with human embryonic kidney 293 cells that had been transiently transfected with the cDNA of Toll-like receptor 2 (TLR2), a cell signaling receptor for PGN, significantly attenuated PGN-induced nuclear factor-kappaB activity. SP-A directly bound to a soluble form of the recombinant extracellular TLR2 domain (sTLR2). Coincubation of sTLR2 with SP-A significantly reduced the binding of sTLR2 to PGN. These results indicate that the direct interaction of SP-A with TLR2 alters PGN-induced cell signaling. We propose that SP-A modulates inflammatory responses against the bacterial components by interactions with pattern-recognition receptors.
authors.affiliation: Department of Biochemistry, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Murakami
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iwaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuzawa
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sano
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Voelker
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Akino
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kuroki
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D002460:Cell Line; D002473:Cell Wall / Q000378:metabolism; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D004492:Edetic Acid / Q000494:pharmacology; D004731:Endotoxins / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011510:Proteolipids / Q000737:chemistry* / Q000378:metabolism*; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D029721:Drosophila Proteins; D004731:Endotoxins; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010457:Peptidoglycan; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C495342:TLR2 protein, human; C495343:Tlr2 protein, rat; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D004492:Edetic Acid