Inactivation of endotoxin by human plasma gelsolin.
Septic shock from bacterial endotoxin, triggered by the release of lipopolysaccharide (LPS) molecules from the outer wall of Gram-negative bacteria, is a major cause of human death for which there is no effective treatment once the complex inflammatory pathways stimulated by these small amphipathic molecules are activated. Here we report that plasma gelsolin, a highly conserved human protein, binds LPS from various bacteria with high affinity. Solid-phase binding assays, fluorescence measurements, and functional assays of actin depolymerizing effects show that gelsolin binds more tightly to LPS than it does to its other known lipid ligands, phosphatidylinositol 4,5-bisphosphate and lysophosphatidic acid. Gelsolin also competes with LPS-binding protein (LBP), a high-affinity carrier for LPS. One result of gelsolin-LPS binding is inhibition of the actin binding activity of gelsolin as well as the actin depolymerizing activity of blood serum. Simultaneously, effects of LPS on cellular functions, including cytoskeletal actin remodeling, and collagen-induced platelet activation by pathways independent of toll-like receptors (TLRs) are neutralized by gelsolin and by a peptide based on gelsolin residues 160-169 (GSN160-169) which comprise part of gelsolin's phosphoinositide binding site. Additionally, TLR-dependent NF-kappaB translocation in astrocytes appears to be blocked by gelsolin. These results show a strong effect of LPS on plasma gelsolin function and suggest that some effects of endotoxin in vivo may be mediated or inhibited by plasma gelsolin.
Bucki
Robert
R
Department of Physiology and Institute for Medicine and Engineering, University of Pennsylvania, 1010 Vagelos Research Laboratories, 3340 Smith Walk, Philadelphia, Pennsylvania 19104, USA. buckirob@ mail.med.upenn.edu
Georges
Penelope C
PC
Espinassous
Quentin
Q
Funaki
Makoto
M
Pastore
Jennifer J
JJ
Chaby
Richard
R
Janmey
Paul A
PA
D008841:Actin Cytoskeleton / Q000378:metabolism; D000209:Acute-Phase Proteins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D018260:Gelsolin / Q000037:antagonists & inhibitors / Q000097:blood* / Q000737:chemistry*; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000097:blood / Q000737:chemistry; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011817:Rabbits; D051381:Rats; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D018260:Gelsolin; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010446:Peptide Fragments; D018129:Phosphatidylinositol Phosphates; D010975:Platelet Aggregation Inhibitors; D000099231:Lipopolysaccharide-Binding Protein