The anti-inflammatory effects of a selectin ligand mimetic, TBC-1269, are not a result of competitive inhibition of leukocyte rolling in vivo.
Selectins and their ligands support leukocyte rolling, facilitating the subsequent firm adhesion and migration that occur during inflammation. TBC-1269 (Bimosiamose), a structural mimetic of natural selectin ligands, inhibits P-, E-, and L-selectin in vitro, has anti-inflammatory effects in vivo, and recently underwent phase II clinical trials for childhood asthma and psoriasis. We studied whether the anti-inflammatory effects of TBC-1269 could be related to leukocyte rolling in vivo. Although TBC-1269 inhibited rolling of a murine leukocyte cell line on murine P-selectin in vitro and thioglycollate-induced peritonitis in vivo, it did not alter leukocyte rolling in mouse cremaster venules. TBC-1269 reduced neutrophil recruitment in thioglycollate-induced peritonitis in wild-type and P-selectin-/- mice but not in E-selectin-/- mice. We suggest that the in vivo effects of TBC-1269 may be mediated through E-selectin but do not appear to involve leukocyte rolling.
Cardiovascular Research Unit, University of Sheffield, United Kingdom.
Anne E R
AE
Hicks
Kate B
KB
Abbitt
Paul
P
Dodd
Victoria C
VC
Ridger
Paul G
PG
Hellewell
Keith E
KE
Norman
D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D019040:E-Selectin / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007249:Inflammation / Q000473:pathology*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008024:Ligands; D008297:Male; D008358:Mannose / Q000031:analogs & derivatives; D008362:Mannosides / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018716:Molecular Mimicry; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019007:P-Selectin / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D034444:Peptoids / Q000737:chemistry / Q000494:pharmacology; D010538:Peritonitis / Q000139:chemically induced / Q000473:pathology; D013864:Thioglycolates / Q000633:toxicity; D014699:Venules / Q000166:cytology
D001713:Biphenyl Compounds; D019040:E-Selectin; D008024:Ligands; D008362:Mannosides; D019007:P-Selectin; D034444:Peptoids; D013864:Thioglycolates; C108700:bimosiamose disodium; D008358:Mannose