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Characterization of two novel LPS-binding sites in leukocyte integrin ßA domain

Kwong-Fai Wong^*,1, John M. Luk^*,,1,2, R. Holland Cheng, Lloyd B. Klickstein and Sheung-Tat Fan^*

^* Department of Surgery, University of Hong Kong, Pokfulam, Hong Kong;

Department of Molecular and Cellular Biology, University of California, Davis, California, USA;

Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

²Correspondence: Department of Surgery, The University of Hong Kong, Jockey Club Clinical Research Center, 21 Sassoon Rd., Pokfulam, Hong Kong. E-mail: jmluk{at}hkucc.hku.hk

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-B 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 ßA region (216–248 and 266–318 a.a.), which were further confirmed by point mutation studies. Inhibition assay demonstrated that the CD18-ßA_266–318 peptide could block LPS binding in a dose-dependent manner. Our data also indicated that treatment with the CD18-peptide modulated TNF- mRNA transcription via the NF-B signaling pathway in LPS-activated Jurkat cells. In conclusion, we have identified two novel LPS-binding sites located at the CD18 ßA domain of leukocyte integrin, and the integrin peptide ßA_266–318 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 ßA domain.

Key Words: lipopolysaccharide • endotoxin-neutralizing peptide • NF-B • sepsis • prophylaxis • TNF-

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