Characterization of two novel LPS-binding sites in leukocyte integrin βA domain
Lipopolysaccharide (LPS), a bacterial endotoxin, triggers deleterious systemic inflammatory responses when released into blood circulation, causing organ dysfunction and death. In response to LPS stimulation, CD14 and toll-like receptor (TLR)-4 elicit inflammatory signaling cascades. Although leukoc...
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Published in | The FASEB journal Vol. 21; no. 12; pp. 3231 - 3239 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
The Federation of American Societies for Experimental Biology
01.10.2007
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Online Access | Get more information |
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Summary: | Lipopolysaccharide (LPS), a bacterial endotoxin, triggers deleterious systemic inflammatory responses when released into blood circulation, causing organ dysfunction and death. In response to LPS stimulation, CD14 and toll-like receptor (TLR)-4 elicit inflammatory signaling cascades. Although leukocyte integrins (CD11b/CD18 and CD11c/CD18) were reported to bind LPS and induce NF-κB translocation, the evidence on such epitope location remains elusive. The present study aims to delineate the LPS-binding sites on the integrin CD18 antigen and to design peptide(s) as potential prophylactic and/or therapeutic agents to modulate LPS effects in activated Jurkat cells. Epitope mapping analysis using a series of CD18 truncated variants revealed two putative LPS-binding sites within the βA region (216-248 and 266-318 a.a.), which were further confirmed by point mutation studies. Inhibition assay demonstrated that the CD18-βA₂₆₆₋₃₁₈ peptide could block LPS binding in a dose-dependent manner. Our data also indicated that treatment with the CD18-peptide modulated TNF-α mRNA transcription via the NF-κB signaling pathway in LPS-activated Jurkat cells. In conclusion, we have identified two novel LPS-binding sites located at the CD18 βA domain of leukocyte integrin, and the integrin peptide βA₂₆₆₋₃₁₈ is shown to inhibit LPS binding and subsequent inflammatory events, having therapeutic implications to cure Gram-negative endotoxemia.-- Wong, K-F, Luk, J. M., Cheng, R. H., Klickstein, L. B., and Fan, S-T. Characterization of two novel LPS-binding sites in leukocyte integrin βA domain. |
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Bibliography: | http://www.fasebj.org/ |
ISSN: | 0892-6638 1530-6860 |
DOI: | 10.1096/fj.06-7579com |