Inhibition of P-selectin specific cell adhesion by a low molecular weight, non-carbohydrate compound, KF38789.
OBJECTIVE
P-selectin is a cell adhesion molecule of the selectin family. This study evaluated the effects of novel, low molecular weight P-selectin inhibitors in a cell adhesion assay and a murine model of peritonitis.


METHODS
U937 or HL60 was used for cell adhesion assay. Human polymorphonuclear cells were studied for the production of superoxide. BALB/c mice were used for the in vivo study.


METHODS
The thioglycollate (TG)-induced accumulation of leukocytes in mice was measured 6 h after the treatment. KF38789 or antibody (1 mg/kg) was injected intravenously prior to TG injection and at 3 h following initial injection.


RESULTS
Low molecular weight, non-carbohydrate inhibitors against P-selectin- mediated cell adhesion were tested. One of the most potent inhibitors, KF38789, inhibited the binding of U937 cells to immobilized P-selectin immunoglobulin G chimeric protein (P-selectin-Ig) with an IC50 value of 1.97 microM. Cell adhesion to both E-selectin-Ig and L-selectin-Ig were not affected even by 100 microM of KF38789. Moreover, KF38789 inhibited P-selectin-induced superoxide production from human polymorphonuclear cells. Intravenously injected KF38789 significantly inhibited the TG-induced accumulation of leukocytes in the mouse peritoneal cavity (p<0.01).


CONCLUSIONS
A novel low molecular weight compound, KF38789, specifically inhibited P-selectin-dependent cell adhesion and the leukocyte recruitment in mouse peritonitis.
Ohta
S
S
Department of Immunology, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Sunto-gun, Shizuoka, Japan. so.ohta@kyowa.co.jp
Inujima
Y
Y
Abe
M
M
Uosaki
Y
Y
Sato
S
S
Miki
I
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009844:Oligosaccharides / Q000378:metabolism; D019007:P-Selectin / Q000187:drug effects* / Q000502:physiology; D010538:Peritonitis / Q000517:prevention & control; D011753:Pyrones / Q000494:pharmacology*; D000080506:Sialyl Lewis X Antigen; D013481:Superoxides / Q000378:metabolism; D013864:Thioglycolates / Q000633:toxicity; D020298:U937 Cells
D000911:Antibodies, Monoclonal; C453959:KF38789; D009844:Oligosaccharides; D019007:P-Selectin; D011753:Pyrones; D000080506:Sialyl Lewis X Antigen; D013864:Thioglycolates; D013481:Superoxides