Hydroxamate-based metalloprotease inhibitor blocks shedding of L-selectin adhesion molecule from leukocytes: functional consequences for neutrophil aggregation.
L-selectin is an adhesion molecule that mediates the recruitment of neutrophils to inflammatory sites and initiates the migration of lymphocytes into the peripheral lymph nodes. In response to cell activation, L-selectin is shed from the cell surface, and altered levels of functional soluble L-selectin are detected in the plasma of patients suffering from numerous inflammatory diseases as well as AIDS. The mechanism that regulates L-selectin shedding is poorly understood. Here we show that a hydroxamate-based metalloprotease inhibitor, N-(D,L-[2-(hydroxyaminocarbonyl)- methyl]-4-methylpentano)-L-3-(tert-butyl)-alanyl-L-alanine, 2-aminoethyl amide, which blocks leukocyte TNF, TNF receptor, and IL-6 receptor release, also inhibits L-selectin shedding from neutrophils, eosinophils, and lymphocytes. Moreover, we show that such inhibition of L-selectin shedding profoundly affects neutrophil aggregation and permits reaggregation in the presence of a heterologous stimulus.
Bennett
T A
TA
Department of Pathology, Cancer Research and Treatment Center, University of New Mexico School of Medicine, Albuquerque 87131, USA.
Lynam
E B
EB
Sklar
L A
LA
Rogelj
S
S
D002449:Cell Aggregation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D019041:L-Selectin / Q000187:drug effects* / Q000502:physiology; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology*
D004151:Dipeptides; D006877:Hydroxamic Acids; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D019041:L-Selectin; D008666:Metalloendopeptidases