title: Peptides from pertussis toxin interfere with neutrophil adherence in vitro and counteract inflammation in vivo.
abstract: Selectins on the surface of endothelial cells initiate leukocyte rolling along the capillary walls during inflammation. The amino acid sequence 19-52 of pertussis toxin subunit S3 is strikingly similar to the sequence 15-46 of the selectins. The S3 subunit inhibits the binding of neutrophils to selectin-coated surfaces and a peptide spanning the 28-45 sequence of S3 reduces leukocyte binding to endothelial cells in vitro and inhibits leukocyte recruitment to the subarachnoid space in vivo. To identify sequences within the 28-45 S3 peptide responsible for these activities, 27 peptides derived by successive truncation of amino acids from either the amino or the carboxyl terminus were tested for anti-inflammatory activity. Truncation at five residues ablated the ability to inhibit neutrophil adherence to endothelial monolayers: valine32, alanine33, arginine36, asparagine38, and threonine43. The most active peptides were either full-length molecules (28-44, 30-45) or short peptides from both ends of the full sequence (39-45, 40-45, 41-45, 28-32). Three peptides with the strongest ability to prevent neutrophil adherence in vitro (28-44, 30-45, 40-45) reduced the cerebrospinal fluid leukocytosis in a pneumococcal meningitis model when administered intravenously. We conclude that peptides derived from a prokaryotic lectin have anti-inflammatory properties consistent with inhibition of selectin participation in leukocyte recruitment during inflammation.
authors.affiliation: Laboratory of Molecular Infectious Diseases, Rockefeller University, New York, NY 10021.
authors.forename: J
authors.initials: J
authors.lastname: Sandros
authors.forename: E
authors.initials: E
authors.lastname: Rozdzinski
authors.forename: E
authors.initials: E
authors.lastname: Tuomanen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D018821:CD18 Antigens; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D007249:Inflammation / Q000517:prevention & control*; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008581:Meningitis / Q000517:prevention & control; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D037342:Pertussis Toxin; D011817:Rabbits; D010566:Virulence Factors, Bordetella / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D010446:Peptide Fragments; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin