Peptides from pertussis toxin interfere with neutrophil adherence in vitro and counteract inflammation in vivo.
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.
Sandros
J
J
Laboratory of Molecular Infectious Diseases, Rockefeller University, New York, NY 10021.
Rozdzinski
E
E
Tuomanen
E
E
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
D015703:Antigens, CD; D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D010446:Peptide Fragments; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin