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* University of Pennsylvania, Institute for Medicine and Engineering, Philadelphia, PA 19104;
Department of Neurology and
Department of Physiology, Medical University of Bialystok, Bialystok, Poland;
European Union Joint Research Centre, Institute for the Protection and Security of the Citizen, the Traceability, Risk and Vulnerability Assessment Unit (TRiVA), Ispra, Italy; and Department of Biochemical Pharmacology, University of Konstanz, Konstanz, Germany
The various functions of gelsolin in extracellular compartments are not yet clearly defined but include actin scavenging and antiinflammatory effects. Gelsolin was recently reported to bind endotoxin (LPS) from various Gram-negative bacteria with high affinity. In this study we investigate whether gelsolin also interacts with bacterial wall molecules of Gram-positive bacteria such as lipoteichoic acid (LTA) and whether gelsolin’s interaction with bacterial lipids from Gram-negative or Gram-positive bacteria affects their cellular inflammatory responses. A peptide based on the PPI binding site of gelsolin (160–169) binds purified LTA at the same molecular ratio that it binds phosphatidylinositol 4,5-bisphosphate. The OD of recombinant human plasma gelsolin was found to decrease following the addition of purified LTA, and the binding of gelsolin to LTA inhibits F-actin depolymerization by gelsolin. Simultaneously, the ability of LTA to activate translocation of NF-
B, E-selectin expression, and adhesion of neutrophils to LTA-treated human aortic endothelial cells was compromised by gelsolin. Gelsolin was able to partially inhibit LPS- or LTA-induced release of IL-8 from human neutrophils but was unable to prevent Gram-positive Bacillus subtilis or Gram-negative Pseudomonas aeruginosa growth and had no effect on the antibacterial activity of the cathelicidin-derived antibacterial peptide LL37. These data suggest that extracellular gelsolin is involved in the host immune recognition of LTA or LPS following release of these molecules from the bacterial outer membrane during cell division or attack by drugs and immune components.
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1 This work was supported by the National Institutes of Health (Grant AR38910), the Cystic Fibrosis Foundation, and the Medical University of Bialystok Grant 3-44903L.
2 Address correspondence and reprint requests to Dr. Robert Bucki, University of Pennsylvania, Institute for Medicine and Engineering, 1010 Vagelos Research Laboratories, 3340 Smith Walk, Philadelphia, PA 19104. E-mail address: buckirob{at}mail.med.upenn.edu
3 Abbreviations used in this paper: ARDS, adult respiratory distress syndrome; CSF, cerebrospinal fluid; DLS, dynamic light scattering; HAEC, human aorta endothelial cells; LBP, LPS-binding protein; LPA, lysophosphatidic acid; LTA, lipoteichoic acid; Malp-2, macrophage-activating lipopeptide-2; MIC, minimal inhibitory concentration; PAF, platelet-activating factor; PBP10, rhodamine B-QRLFQVKGRR; PIP2, phosphatidylinositol 4,5-bisphosphate; RhB, rhodamine B; rhGSN, recombinant human plasma gelsolin.
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