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CD14 Employs Hydrophilic Regions to "Capture" Lipopolysaccharides

Mark D. Cunningham^*, Robert A. Shapiro, Carrie Seachord^*, Kent Ratcliffe, Linda Cassiano and Richard P. Darveau^1,§

^* Bristol-Myers Squibb Pharmaceutical Research Institute, Lawrenceville, NJ 08543; Immunex Corp., Seattle, WA 98101; and Departments of Psychiatry and Behavioral Sciences and ^§ Periodontics, University of Washington, Seattle, WA 98195

CD14 participates in the host innate inflammatory response to bacterial LPS obtained from Escherichia coli and other Gram-negative bacteria. Evidence from several laboratories suggests that different regions of the amino-terminal portion of the molecule may be involved in LPS binding. In this report a series of single-residue serine replacement and charge reversal mutations were generated to further elucidate the mechanism by which this protein may bind a multitude of different LPS ligands. Single-residue CD14 mutation proteins were examined for their ability to bind LPS obtained from E. coli, Porphyromonas gingivalis, and Helicobacter pylori and facilitate the activation of E-selectin from human endothelial cells. In addition, the single-residue CD14 mutation proteins were employed to perform monoclonal epitope-mapping studies with three LPS-blocking Abs that bound tertiary epitopes. Evidence that several different hydrophilic regions of the amino-terminal region of CD14 are involved in LPS binding was obtained. Epitope-mapping studies revealed that these hydrophilic regions are located on one side of the protein surface. These studies suggest that CD14 employs a charged surface in a manor similar to the macrophage scavenger receptor to "capture" LPS ligands and "present" them to other components of the innate host defense system.