Transendothelial migration of neutrophils involves integrin-associated protein (CD47).
Inflammation is a primary pathological process. The development of an inflammatory reaction involves the movement of white blood cells through the endothelial lining of blood vessels into tissues. This process of transendothelial cell migration of neutrophils has been shown to involve neutrophil beta 2 integrins (CD18) and endothelial cell platelet-endothelium cell adhesion molecules (PECAM-1; CD31). We now show that F(ab')2 fragments of the monoclonal antibody B6H12 against integrin-associated protein (IAP) blocks the transendothelial migration of neutrophils stimulated by an exogenous gradient of the chemokine interleukin 8 (IL-8; 60% inhibition), by the chemotactic peptide N-formyl-methionylleucylphenylalanine (FMLP; 76% inhibition), or by the activation of the endothelium by the cytokine tumor necrosis factor alpha (98% inhibition). The antibody has two mechanisms of action: on neutrophils it prevents the chemotactic response to IL-8 and FMLP, and on endothelium it prevents an unknown but IL-8-independent process. Blocking antibodies to IAP do not alter the expression of adhesion proteins or production of IL-8 by endothelial cells, and thus the inhibition of neutrophil transendothelial migration is selective. These data implicate IAP as the third molecule essential for neutrophil migration through endothelium into sites of inflammation.
Cooper
D
D
Hanson Centre for Cancer Research, Adelaide, Australia.
Lindberg
F P
FP
Gamble
J R
JR
Brown
E J
EJ
Vadas
M A
MA
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology / Q000502:physiology; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology; D016209:Interleukin-8 / Q000032:analysis / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D007140:Immunoglobulin Fab Fragments; D016209:Interleukin-8; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine